Professor Hubert Hondermarck

Professor Hubert Hondermarck

Professor

School of Biomedical Sciences and Pharmacy (Medical Biochemistry)

Career Summary

Biography

Hubert Hondermarck obtained a PhD in neurobiochemistry at the University of Lille in France (1990) and was a post-doctoral researcher at the University of California in Irvine (1990-1993) where he investigated the molecular mechanisms of neuronal cell differentiation using proteomics. He founded a research unit of the French Institute of Health and Medical Research (U908 INSERM) dedicated to the study of growth factor signaling and functional proteomics in breast cancer. In 2011, he relocated to the University of Newcastle to start a new program on the function of neurotrophic growth factors and the impact of the nervous system in cancer initiation and progression.

Research Expertise: Cancer Neurobiology and Proteomics

Hubert Hondermarck research group works on the crosstalk between nerves and cancer cells, and its impact on tumour growth and metastasis. Until recently neurons were thought not to be involved in cancer. However, recent evidence in prostate and breast cancers, including from our laboratory, have shown that nerves actually promote tumour progression and that denervation can suppress both the development of the primary tumor and the outburst of metastases. The objective of this research is to identify the molecular mediators of the cross-talk between nerves and cancer cells that may constitute new and innovative biomarkers and therapeutic targets in oncology. Our methodologies include the analysis of human tumour samples, cell cultures,  proteomics and mass spectrometry analysis. We work in collaboration with neurobiologists, pathologists, clinicians and private companies to translate the results of our research into practical outcomes in oncology.

                    

Figure: Nerve-cancer cell crosstalk.Nerves infiltrate the tumor microenvironment and stimulate cancer cell growth and metastasis through the secretion of neurotransmitters (such as catecholamines, acetylcholine and neuropeptides) initiating signaling pathways for growth and invasion in cancer cells after binding to neurotransmitter receptors (NTRs). Conversely, nerve infiltration in the tumor is mediated through the liberation of neurotrophic growth factors (such as NGF) by cancer cells, resulting in neuron outgrowth (axonogenesis or neo-neurogenesis), as well as autocrine stimulation of cancer cells via the stimulation of corresponding receptor tyrosine kinases (RTKs). This reciprocal interaction fuels tumor development and also impacts the microenvironment, as the liberated neurotransmitters and growth factors can also act on endothelial and immune cells, then contributing to tumor inflammation and neo-angiogenesis. Cancer-induced pain can also be a consequence of tumor innervation. PLCγ, phospholipase C gamma; cAMP, cyclic adenosine monophosphate; STAT, signal transducer activator of transcription; PKC, protein kinase C; MAPK, mitogen-activated protein kinases. From our review Jobling et al. Cancer Res. (2015).

Scientific production

Hubert Hondermarck has published 91 PubMed referenced articles on cancer cell biology and proteomics http://www.ncbi.nlm.nih.gov/pubmed?term=hondermarck, and 2 internationally issued patents in collaboration with biopharmaceutical companies.

Most recent publications 

Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell. 2017 31:342-354.

Faulkner S, Roselli S, Demont Y, Pundavela J, Choquet G, Leissner P, Oldmeadow C, Attia J, Walker MM, Hondermarck H.ProNGF is a potential diagnostic biomarker for thyroid cancer. Oncotarget. 2016 7:28488-97.

Shargh VH, Hondermarck H, Liang M. Albumin hybrid nanoparticles loaded with tyrosine kinase A inhibitor GNF-5837 for targeted inhibition of breast cancer cell growth and invasion. Int J Pharm. 2016 515:527-534.

Jobling P, Pundavela J, Oliverira SMR, Roselli S, Walker MM, Hondermarck H. Nerve-cancer cell crosstalk: a novel promoter of tumor progression. Cancer Res. 2015, 75, 1-5.

Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, Bradshaw RA, Walker MM, Jobling P, Hondermarck H. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Molecular Oncol. 2015, 9(8):1626-35.

Dun MD, Chalkley RJ, Faulkner S, Keene S, Avery-Kiejda K, Scott RJ, Falkenby LG, Cairns MJ, Larsen MR, Bradshaw RA, Hondermarck
H. Proteotranscriptomic profiling of 231-BR breast cancer cells: identification of potential biomarkers and therapeutic targets for brain metastasis. Mol Cell Proteomics. 2015, 14(9):2316-30.

Roselli S, Pundavela J, Demont Y, Faulkner S, Sheridan K, AttiaJ, Jiang CC, Zhang XD, Walker MM, Hondermarck H. Sortilin is associated with breast cancer aggressiveness and contributes to tumour cell adhesion and invasion. Oncotarget 2015, 6(12):10473-86.

Faulkner, S., Dun, M.D., Hondermarck, H. Proteogenomics: emergence and promise. Cell Mol Life Sci. 2015, 72(:953-7.

Pundavela J, Demont Y, Jobling P, Lincz LF, Roselli S, Thorne RF, Bond D, Bradshaw RA, Walker MM, Hondermarck H. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am J Pathol. 2014, 184, 3156-62.

Editorial boards

Hubert Hondermarck is a member of the Board of the following Journals: Molecular and Cellular Proteomics (ASBMB), Proteomics Clinical Applications (Wiley), Open Cancer Journal (Bentham) and Frontiers in Endocrinology (Frontiers Media).

Teaching Expertise

Biochemistry, proteomics, cancer biology, bioinformatics.

Course coordinator: HUBS3302 Bioinformatic and functional genomics. HUBS3409. Projects in Biomedical Sciences.

HUBS2209. Human Molecular Sciences.

Administrative Activities

Head of the Discipline of Medical Biochemistry (Faculty of Health and Medicine).


Qualifications

  • PhD (Life Sciences & Health), University of Lille - France

Keywords

  • Cancer biology
  • Cellular and molecular biology
  • Growth factors
  • Proteomics
  • Translational cancer research

Languages

  • French (Mother)

Fields of Research

Code Description Percentage
110106 Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics) 40
111201 Cancer Cell Biology 60

Professional Experience

UON Appointment

Title Organisation / Department
Professor University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Book (1 outputs)

Year Citation Altmetrics Link
1997 Bradshaw RA, Hondermarck H, Nerve growth factor receptors (1997)
DOI 10.1016/S1874-5342(96)80036-5
Citations Scopus - 1

Chapter (3 outputs)

Year Citation Altmetrics Link
2016 Milward EA, Shahandeh A, Heidari M, Johnstone DM, Daneshi N, Hondermarck H, 'Transcriptomics', Encyclopedia of Cell Biology, Elsevier, The Netherland 160-165 (2016)
DOI 10.1016/B978-0-12-394447-4.40029-5
Co-authors Liz Milward
2015 Hondermarck H, Demont Y, Bradshaw RA, 'The TrK receptor family', Receptor Tyrosine Kinases: Family and Subfamilies, Springer, New York 777-820 (2015) [B1]
DOI 10.1007/978-3-319-11888-8_17
Citations Scopus - 2
2010 Hondermarck H, '14-3-3 proteins', Handbook of Cell Signaling, 2/e 1367-1374 (2010)

14-3-3 proteins are highly conserved and ubiquitously expressed proteins, which are found in all eukaryotic cells, and not in bacteria. There are seven isoforms (ß, ¿, e, ¿, ¿... [more]

14-3-3 proteins are highly conserved and ubiquitously expressed proteins, which are found in all eukaryotic cells, and not in bacteria. There are seven isoforms (ß, ¿, e, ¿, ¿, t/¿, and ¿, with a and d, corresponding to the phosphorylated forms of ß and ¿ respectively) in mammals, each encoded by a distinct gene. The binding of 14-3-3 proteins is primarily phosphorylation dependent; therefore 14-3-3 interactions are largely regulated by the kinases and phosphatases that modulate the phosphorylation state of a target protein. Binding partners include signaling proteins that are involved in various pathways leading to the control or modulation of cell survival, growth, migration, and differentiation. One of the interventions of 14-3-3 proteins in cell signaling is the regulation of the serine/threonine kinase Raf1. 14-3-3 proteins can stimulate the transformation between the inactive and active forms of Raf1 and mediate the association of Raf1 with other proteins that activate Raf1, such as protein kinase C (PKC), Bcr, and the KSR kinase suppressor of Ras. 14-3-3 proteins are involved in controlling the function and localization of related ion channels such as the ¿ and e forms can regulate TWIK-related spinal cord K(+) channel (TRESK) and the regulation of epithelial sodium channel by aldosterone requires the ß and d forms of 14-3-3e. This ability to regulate ion channels is of crucial importance in the nervous system, in which 14-3-3 proteins participate in synaptic t ransmission and plasticity. © 2010 Elsevier Inc. All rights reserved.

DOI 10.1016/B978-0-12-374145-5.00169-8

Journal article (105 outputs)

Year Citation Altmetrics Link
2017 Rougemont B, Gallo SB, Ayciriex S, Carriere R, Hondermarck H, Lacroix JM, et al., 'Scout-MRM: Multiplexed Targeted Mass Spectrometry-Based Assay without Retention Time Scheduling Exemplified by Dickeya dadantii Proteomic Analysis during Plant Infection', ANALYTICAL CHEMISTRY, 89 1421-1426 (2017)
DOI 10.1021/acsanalchem.6b03201
2017 Faulkner S, Jobling P, Rowe C, Rodriguez-Oliveira S, Roselli S, Thorne R, et al., 'Neurotrophin Receptors TrkA, p75(NTR), and Sortilin are Increased and Targetable in Thyroid Cancer.', Am J Pathol, (2017)
DOI 10.1016/j.ajpath.2017.09.008
2017 Rougemont B, Bontemps Gallo S, Ayciriex S, Carrière R, Hondermarck H, Lacroix JM, et al., 'Scout-MRM: Multiplexed Targeted Mass Spectrometry-Based Assay without Retention Time Scheduling Exemplified by Dickeya dadantii Proteomic Analysis during Plant Infection.', Anal Chem, 89 1421-1426 (2017)
DOI 10.1021/acs.analchem.6b03201
2017 Guo ST, Guo XY, Wang J, Wang CY, Yang RH, Wang FH, et al., 'MicroRNA-645 is an oncogenic regulator in colon cancer.', Oncogenesis, 6 e335 (2017)
DOI 10.1038/oncsis.2017.37
Co-authors Xu Zhang, Lei Jin, Chenchen Jiang, Rick Thorne
2017 Shargh VH, Hondermarck H, Liang M, 'Gelatin-albumin hybrid nanoparticles as matrix metalloproteinases-degradable delivery systems for breast cancer therapy.', Nanomedicine (Lond), 12 977-989 (2017)
DOI 10.2217/nnm-2016-0419
Co-authors Roger Liang
2017 Boilly B, Faulkner S, Jobling P, Hondermarck H, 'Nerve Dependence: From Regeneration to Cancer.', Cancer Cell, 31 342-354 (2017)
DOI 10.1016/j.ccell.2017.02.005
Citations Scopus - 2Web of Science - 2
Co-authors Phillip Jobling
2017 de Bock CE, Hughes MR, Snyder K, Alley S, Sadeqzadeh E, Dun MD, et al., 'Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels', FEBS LETTERS, 591 667-678 (2017) [C1]
DOI 10.1002/1873-3468.12569
Co-authors Matt Dun, Rick Thorne
2016 Faulkner S, Roselli S, Demont Y, Pundavela J, Choquet G, Leissner P, et al., 'ProNGF is a potential diagnostic biomarker for thyroid cancer', Oncotarget, 7 28488-28497 (2016) [C1]

The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopatho... [more]

The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopathological significance of proNGF in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign tumors (adenoma) and normal thyroid tissues. In the first cohort (40 thyroid cancers, 40 thyroid adenomas and 80 normal thyroid tissues), proNGF was found overexpressed in cancers compared to adenomas and normal samples (p < 0.0001). The area under the receiver-operating characteristic (ROC) curve was 0.84 (95% CI 0.75-0.93, p < 0.0001) for cancers versus adenomas, and 0.99 (95% CI 0.98-1.00, p < 0.0001) for cancers versus normal tissues. ProNGF overexpression was confirmed in a second cohort (127 cancers of various histological types and 55 normal thyroid tissues) and using a different antibody (p < 0.0001). ProNGF staining intensity was highest in papillary carcinomas compared to other histological types (p < 0.0001) and there was no significant association with age, gender, tumor size, stage and lymph node status. In conclusion, proNGF is increased in thyroid cancer and should be considered as a new potential diagnostic biomarker.

DOI 10.18632/oncotarget.8652
Citations Scopus - 2Web of Science - 1
Co-authors Christopher Oldmeadow, Marjorie Walker, John Attia
2016 Hetherington L, Schneider EK, DeKretser D, Muller CH, Hondermarck H, Velkov T, et al., 'Deficiency in outer dense fiber 1 is a marker and potential driver of idiopathic male infertility', Molecular and Cellular Proteomics, 15 3685-3693 (2016) [C1]

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Globally, ~1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their ... [more]

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Globally, ~1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their gamete failure are unknown. Although a semen analysis is performed to determine fertilizing potential, the diagnostic suitability of this analysis has been questioned in several reports, as many men, classified as infertile according to their semen analysis, subsequently turn out to be fertile. Herein, we have used a quantitative (phospho)-proteomic analysis, using enrichment on titanium dioxide followed by ion-trap mass spectrometry (LC-MS/MS), to compare the semen of infertile versus fertile males. One prote in, namely outer dense fiber 1 (ODF1), was dramatically reduced in infertile males. Using specific antibodies, we then screened the gametes of a cohort of suspected infertile men and demonstrated a reduction in the amount of ODF1 compared with fertile controls. Stress treatment of sperm deficient in ODF1 caused the head to decapitate, suggesting why these gametes fail to initiate fertilization. Interestingly, electron micrographs of ODF1-deficient spermatozoa revealed an abnormal connecting piece, indicating several developmental defects with both the implantation plate and the thin laminated fibers. In some cases, the implantation plate appeared to be reduced in size or was overburdened by granular material near the connecting piece. Hence, a strong reduction ODF1 is a marker of idiopathic male infertility and a potential driver of this condition.

DOI 10.1074/mcp.M116.060343
Citations Scopus - 1Web of Science - 1
Co-authors Mark Baker
2016 Shargh VH, Hondermarck H, Liang M, 'Antibody-targeted biodegradable nanoparticles for cancer therapy', Nanomedicine, 11 63-79 (2016) [C1]

© 2016 Future Medicine Ltd. The use of nanotechnology has great potentials to revolutionize the future cancer diagnosis and therapy. In this context, various nanoparticles (NPs) ... [more]

© 2016 Future Medicine Ltd. The use of nanotechnology has great potentials to revolutionize the future cancer diagnosis and therapy. In this context, various nanoparticles (NPs) have been developed for targeted delivery of diagnostic/therapeutic agents to the tumor sites, which thus result in greater efficacy and much less side effects. The targeting property of NPs is often achieved by functionalizing their surface with tumor-specific ligands, such as antibodies, peptides, small molecules and oligonucleotides. In this review, we will discuss recent progress in the multifunctional design of antibody-targeted NPs with a special focus on liposomal, polymeric and protein-based delivery systems.

DOI 10.2217/nnm.15.186
Citations Scopus - 11Web of Science - 9
Co-authors Roger Liang
2016 Guo ST, Chi MN, Yang RH, Guo XY, Zan LK, Wang CY, et al., 'INPP4B is an oncogenic regulator in human colon cancer', Oncogene, 35 3049-3061 (2016) [C1]

© 2016 Macmillan Publishers Limited. All rights reserved. Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and i... [more]

© 2016 Macmillan Publishers Limited. All rights reserved. Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum-and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.

DOI 10.1038/onc.2015.361
Citations Scopus - 6Web of Science - 7
Co-authors Stephen Ackland, Rick Thorne, Rodney Scott, Lei Jin, Chenchen Jiang, Xu Zhang
2016 Shargh VH, Hondermarck H, Liang M, 'Albumin hybrid nanoparticles loaded with tyrosine kinase A inhibitor GNF-5837 for targeted inhibition of breast cancer cell growth and invasion.', Int J Pharm, 515 527-534 (2016) [C1]
DOI 10.1016/j.ijpharm.2016.10.057
Citations Scopus - 2Web of Science - 2
Co-authors Roger Liang
2015 Dun MD, Chalkley RJ, Faulkner S, Keene S, Avery-Kiejda KA, Scott RJ, et al., 'Proteotranscriptomic profiling of 231-BR breast cancer cells: Identification of potential biomarkers and therapeutic targets for brain metastasis', Molecular and Cellular Proteomics, 14 2316-2330 (2015) [C1]

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Brain metastases are a devastating consequence of cancer and currently there are no specific biomarker... [more]

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and L-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation.

DOI 10.1074/mcp.M114.046110
Citations Scopus - 8Web of Science - 9
Co-authors Matt Dun, Kelly Kiejda, Rodney Scott, Murray Cairns
2015 Roselli S, Pundavela J, Demont Y, Faulkner S, Keene S, Attia J, et al., 'Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion', Oncotarget, 6 10473-10486 (2015) [C1]

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed... [more]

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.

Citations Scopus - 5Web of Science - 5
Co-authors Chenchen Jiang, John Attia, Marjorie Walker, Xu Zhang
2015 Bradshaw RA, Pundavela J, Biarc J, Chalkley RJ, Burlingame AL, Hondermarck H, 'NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling', Advances in Biological Regulation, 58 16-27 (2015) [C1]

© 2014 Elsevier Ltd. Nerve growth factor (NGF) and its precursor (proNGF) are primarily considered as regulators of neuronal function that induce their responses via the tyrosine... [more]

© 2014 Elsevier Ltd. Nerve growth factor (NGF) and its precursor (proNGF) are primarily considered as regulators of neuronal function that induce their responses via the tyrosine kinase receptor TrkA and the pan-neurotrophin receptor p75NTR. It has been generally held that NGF exerts its effects primarily through TrkA, inducing a cascade of tyrosine kinase-initiated responses, while proNGF binds more strongly to p75NTR. When this latter entity interacts with a third receptor, sortilin, apoptotic responses are induced in contrast to the survival/differentiation associated with the other two. Recent studies have outlined portions of the downstream phosphoproteome of TrkA in the neuronal PC12 cells and have clarified the contribution of individual docking sites in the TrkA endodomain. The patterns observed showed a similarity with the profile induced by the epidermal growth factor receptor, which is extensively associated with oncogenesis. Indeed, as with other neurotrophic factors, the distribution of TrkA and p75NTR is not limited to neuronal tissue, thus providing an array of targets outside the nervous systems. One such source is breast cancer cells, in which NGF and proNGF stimulate breast cancer cell survival/growth and enhance cell invasion, respectively. This latter activity is exerted via TrkA (as opposed to p75NTR) in conjunction with sortilin. Another tissue overexpressing proNGF is prostate cancer and here the ability of cancer cells to induce neuritogenesis has been implicated in cancer progression. These studies show that the non-neuronal functions of proNGF/NGF are likely integrated with their neuronal activities and point to the clinical utility of these growth factors and their receptors as biomarkers and therapeutic targets for metastasis and cancer pain.

DOI 10.1016/j.jbior.2014.11.003
Citations Scopus - 20
2015 Blanckaert V, Kerviel V, Lépinay A, Joubert-Durigneux V, Hondermarck H, Chénais B, 'Docosahexaenoic acid inhibits the invasion of MDA-MB-231 breast cancer cells through upregulation of cytokeratin-1.', Int J Oncol, 46 2649-2655 (2015) [C1]
DOI 10.3892/ijo.2015.2936
Citations Scopus - 2Web of Science - 2
2015 Faulkner S, Dun MD, Hondermarck H, 'Proteogenomics: Emergence and promise', Cellular and Molecular Life Sciences, 72 953-957 (2015) [C1]

© Springer Basel 2015. Proteogenomics, or the integration of proteomics with genomics and transcriptomics, is emerging as the next step towards a unified understanding of cellula... [more]

© Springer Basel 2015. Proteogenomics, or the integration of proteomics with genomics and transcriptomics, is emerging as the next step towards a unified understanding of cellular functions. Looking globally and simultaneously at gene structure, RNA expression, protein synthesis and posttranslational modifications have become technically feasible and offer a new perspective to molecular processes. Recent publications have highlighted the value of proteogenomics in oncology for defining the molecular signature of human tumors, and translation to other areas of biomedicine and life sciences is anticipated. This minireview will discuss recent developments, challenges and perspectives in proteogenomics.

DOI 10.1007/s00018-015-1837-y
Citations Scopus - 15Web of Science - 16
Co-authors Matt Dun
2015 Jobling P, Pundavela J, Oliveira SMR, Roselli S, Walker MM, Hondermarck H, 'Nerve-Cancer Cell Cross-talk: A Novel Promoter of Tumor Progression', CANCER RESEARCH, 75 1777-1781 (2015) [C1]
DOI 10.1158/0008-5472.CAN-14-3180
Citations Scopus - 23Web of Science - 23
Co-authors Marjorie Walker, Phillip Jobling
2015 Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al., 'Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer', Molecular Oncology, 9 1626-1635 (2015) [C1]
DOI 10.1016/j.molonc.2015.05.001
Citations Scopus - 3Web of Science - 2
Co-authors Marjorie Walker, John Forbes, Rodney Scott, Phillip Jobling, John Attia, Rick Thorne
2015 Ahmed AF, De Bock CE, Lincz LF, Pundavela J, Zouikr I, Sontag E, et al., 'FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation', Cellular and Molecular Life Sciences, 72 4653-4669 (2015) [C1]

© 2015 Springer Basel. The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebra... [more]

© 2015 Springer Basel. The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.

DOI 10.1007/s00018-015-1955-6
Citations Scopus - 8Web of Science - 5
Co-authors Estelle Sontag, Lisa Lincz, Rick Thorne
2015 Jiang C, Chi MN, Guo ST, Wilmott JS, Guo X Y, Yan X G, et al., 'INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas', Oncotarget, 6 39891-39907 (2015) [C1]
DOI 10.18632/oncotarget.5359
Citations Scopus - 11Web of Science - 9
Co-authors Lei Jin, Xu Zhang, Chenchen Jiang
2014 Pundavela J, Demont Y, Jobling P, Lincz LF, Roselli S, Thorne RF, et al., 'ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer', American Journal of Pathology, 184 3156-3162 (2014) [C1]

© 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Nerve infiltration is essential to prostate cancer progression, but the mecha... [more]

© 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, t < inf > B < /inf > = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of =8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves.

DOI 10.1016/j.ajpath.2014.08.009
Citations Scopus - 9Web of Science - 6
Co-authors Rick Thorne, Phillip Jobling, Lisa Lincz, Marjorie Walker, Danielle Bond
2013 Bailly F, Toillon R-A, Tomavo O, Jouy N, Hondermarck H, Cotelle P, 'Antiproliferative and apoptotic effects of the oxidative dimerization product of methyl caffeate on human breast cancer cells', BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 23 574-578 (2013) [C1]
DOI 10.1016/j.bmcl.2012.11.009
Citations Scopus - 8Web of Science - 7
2012 Demont Y, Corbet C, Page A, Ataman-Onal Y, Choquet-Kastylevsky G, Fliniaux I, et al., 'Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase A (TrkA) and sortilin protein', Journal of Biological Chemistry, 287 1923-1931 (2012) [C1]
Citations Scopus - 31Web of Science - 25
2011 Hondermarck H, 'Proteomics and target identification in oncology', European Pharmaceutical Review, (2011)

The recent progresses in the field of proteomics now enable large scale, high throughput, sensitive and quantitative protein analysis. Therefore, applying proteomics in clinical o... [more]

The recent progresses in the field of proteomics now enable large scale, high throughput, sensitive and quantitative protein analysis. Therefore, applying proteomics in clinical oncology becomes realistic. From the analysis of cell cultures to biological fluids and tumour biopsies, proteomic investigations of cancers are flourishing and new candidate biomarkers and therapeutic targets are slowly emerging. In the meantime, what we know of the cancer proteome is also an evolving figure that is progressively unveiled. Given the multiparametric nature and diversity of cancers, it should not be underestimated that a great deal of time and effort will be necessary for translating that knowledge into practical applications in oncology. © Russell Publishing Limited, 2010, 2011. All rights reserved.

2011 Wilmet J-P, Tastet C, Desruelles E, Ziental-Gelus N, Blanckaert V, Hondermarck H, Le Bourhis X, 'Proteome changes induced by overexpression of the p75 neurotrophin receptor (p75(NTR)) in breast cancer cells', INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY, 55 801-809 (2011) [C1]
DOI 10.1387/ijdb.113345jw
Citations Scopus - 7Web of Science - 6
2011 Vanhecke E, Adriaenssens E, Verbeke S, Meignan S, Germain E, Berteaux N, et al., 'Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival', Clinical Cancer Research, 17 1741-1752 (2011) [C1]

Purpose: Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT)... [more]

Purpose: Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT) are expressed and have an influence in breast tumor growth. Experimental Design: The expression of brain-derived neurotrophic factor (BDNF), NT-3 and NT-4/5, as well as the neurotrophin receptor p75 NTR , TrkB, and TrkC, was studied by RT-PCR, Western blotting, and immunohistochemistry in cell lines and tumor biopsies. The biological impacts of neurotrophins, and associated mechanisms, were analyzed in cell cultures and xenografted mice. Results: BDNF and NT-4/5 were expressed and secreted by breast cancer cells, and the use of blocking antibodies suggested an autocrine loop mediating cell resistance to apoptosis. The corresponding tyrosine kinase receptor TrkB was only rarely observed at full length, whereas the expression of TrkB-T1, lacking the kinase domain, as well as p75 NTR , were detected in all tested breast cancer cell lines and tumor biopsies. In contrast, NT-3 and TrkC were not detected. SiRNA against p75 NTR and TrkB-T1 abolished the antiapoptotic effect of BDNF and NT-4/5, whereas the pharmacological inhibitors K252a and PD98059 had no effect, suggesting the involvement of p75 NTR and TrkB-T1, but not kinase activities from Trks and MAPK. In xenografted mice, anti-BDNF, anti-NT-4/5, anti-p75 NTR , or anti-TrkB-T1 treatments resulted in tumor growth inhibition, characterized by an increase in cell apoptosis, but with no change in proliferation. Conclusion: BDNF and NT-4/5 contribute to breast cancer cell survival and can serve as prospective targets in attempts to inhibit tumor growth. ©2011 AACR.

DOI 10.1158/1078-0432.CCR-10-1890
Citations Scopus - 51
2010 Lagadec C, Romon R, Tastet C, Meignan S, Com E, Page A, et al., 'Ku86 is important for TrkA overexpression-induced breast cancer cell invasion', Proteomics - Clinical Applications, 4 580-590 (2010) [C1]

Purpose: We have recently shown that breast tumors express high levels of TrkA compared with normal breast tissues, with TrkA overexpression enhancing breast cancer cell invasion ... [more]

Purpose: We have recently shown that breast tumors express high levels of TrkA compared with normal breast tissues, with TrkA overexpression enhancing breast cancer cell invasion in vitro and metastasis in animal models. In this study, we tried to identify molecules involved in TrkA overexpression-mediated biological effects in breast cancer cells. Experimental design: We used a proteomic-based approach to identify proteins involved in TrkA overexpression-stimulated invasion of MDA-MB-231 breast cancer cells. Proteins from control and TrkA overexpressing cells were separated using a cup-loading two-dimensional electrophoresis system before MALDI and LC-MS/MS mass spectrometry analysis. Results: Among several putative regulated proteins, Ku86 was found increased in TrkA overexpressing cells. Moreover, Ku86 was co-immunoprecipitated with TrkA, suggesting the interaction of these two proteins in TrkA overexpressing cells. Interestingly, inhibition with small-interfering RNA and neutralizing antibodies showed that Ku86 was required for TrkAstimulated cell invasion. Conclusions and clinical relevance: These data allowed the identification of Ku86 as a new player involved in metastasis in breast cancer cells. Our findings suggest that TrkA and its down stream signaling pathways sho uld be regarded as potential new targets for the development of future breast cancer therapy. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI 10.1002/prca.200900148
Citations Scopus - 9
2010 Romon R, Adriaenssens E, Lagadec C, Germain E, Hondermarck H, Le Bourhis X, 'Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways', Molecular Cancer, 9 (2010) [C1]
DOI 10.1186/1476-4598-9-157
Citations Scopus - 60
2010 Le Bourhis X, Romon R, Hondermarck H, 'Role of endothelial progenitor cells in breast cancer angiogenesis: From fundamental research to clinical ramifications', Breast Cancer Research and Treatment, 120 17-24 (2010) [C1]

Blood vessel formation (neovascularization) in tumors can occur through two mechanisms: angiogenesis and vasculogenesis. Angiogenesis results from proliferation and sprouting of e... [more]

Blood vessel formation (neovascularization) in tumors can occur through two mechanisms: angiogenesis and vasculogenesis. Angiogenesis results from proliferation and sprouting of existing blood vessels close to the tumor, while vasculogenesis is believed to arise from recruitment of circulating cells, largely derived from the bone marrow, and de novo clonal formation of blood vessels from these cells. Increasing evidence in animal models indicate that bone marrow-derived endothelial precursor cells (EPC) can contribute to tumor angiogenesis. This review aims to collate existing literature and provide an overview on the current knowledge of EPC involvement in breast cancer angiogenesis. We also discuss recent attempts to use EPC as biomarker and therapeutic target in clinical trials. © 2009 Springer Science+Business Media, LLC.

DOI 10.1007/s10549-009-0686-5
Citations Scopus - 21
2010 Verbeke S, Meignan S, Lagadec C, Germain E, Hondermarck H, Adriaenssens E, Le Bourhis X, 'Overexpression of p75

The p75 neurotrophin receptor (p75 NTR ) plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation and proliferation. To e... [more]

The p75 neurotrophin receptor (p75 NTR ) plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation and proliferation. To evaluate the influence of p75 NTR in breast cancer development, we have established and characterized breast cancer cells which stably overexpress p75 NTR . We showed that p75 NTR overexpression per se promoted cell survival to apoptogens with a concomitant slowdown of cell growth. The pro-survival effect is associated with an increased expression of the inhibitor of apoptosis protein-1 (c-IAP1), a decrease of TRAIL-induced cleavage of PARP, procaspase 9 and procaspase 3, and a decrease of cytochrome C release from the mitochondria. The anti-proliferative effect is due to a cell accumulation in G0/G1, associated with a decrease of Rb phosphorylation and an increase of p21 waf1 . Interestingly, inhibition of p21 waf1 with siRNA not only restores proliferation but also abolishes the pro-survival effect of p75 NTR , indicating the key role of p21 waf1 in the biological functions of p75 NTR . Finally, using a SCID mice xenograft model, we showed that p75 NTR overexpression favors tumor growth and strongly increases tumor resistance to anti-tumoral treatment.Together, our findings suggest that p75 NTR overexpression in breast tumor cells could favor tumor survival and contribute to tumor resistance to drugs. This provides a rationale to consider p75 NTR as a potential target for the future design of innovative therapeutic strategies. © 2010 Elsevier Inc.

DOI 10.1016/j.cellsig.2010.07.014
Citations Scopus - 35
2009 Collins BC, Lau TYK, O'Connor DP, Hondermarck H, 'Cancer proteomics - An evolving battlefield: Conference on cancer proteomics 2009: Mechanistic insights, technological advances & molecular medicine', EMBO Reports, 10 1202-1205 (2009) [E3]
DOI 10.1038/embor.2009.222
Citations Scopus - 7
2009 Joubel A, Chalkley RJ, Medzihradszky KF, Hondermarck H, Burlingame AL, 'Identification of new p53 acetylation sites in COS-1 cells', Molecular and Cellular Proteomics, 8 1167-1173 (2009) [C1]

The p53 tumor suppressor protein is a key regulator of cell cycle and death that is involved in many cell signaling pathways and is tightly regulated in mammalian cells. Post-tran... [more]

The p53 tumor suppressor protein is a key regulator of cell cycle and death that is involved in many cell signaling pathways and is tightly regulated in mammalian cells. Post-translational modifications of p53 have been investigated previously mainly using antibodies. In this study, utilizing LC-MS/MS analysis, we have characterized p53 protein from COS-1 cells. Several already known posttranslational modifications were observed, such as phosphorylation on serines 15, 33, 315, and 392 as well as acetylation on lysines 305, 370, 372, 373, 381, 382, and 386. Interestingly novel acetylation sites were identified at lysines 319 and 357. This study confirmed that p53 is a highly acetylated protein and revealed new acetylation sites that might aid the further understanding of p53 regulation. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/mcp.M800487-MCP200
Citations Scopus - 10
2009 Strande V, Canelle L, Tastet C, Burlet-Schiltz O, Monsarrat B, Hondermarck H, 'The proteome of the human breast cancer cell line MDA-MB-231: Analysis by LTQ-Orbitrap mass spectrometry', Proteomics - Clinical Applications, 3 41-50 (2009) [C1]

We have used a combination of SDS-PAGE and LTQ-Orbitrap MS to explore the proteome of the highly invasive MDA-MB-231 breast cancer cell line. Based on about 520 000 MS/MS spectra,... [more]

We have used a combination of SDS-PAGE and LTQ-Orbitrap MS to explore the proteome of the highly invasive MDA-MB-231 breast cancer cell line. Based on about 520 000 MS/MS spectra, a total of 3481 proteins were identified and subsequently classified according to their cellular distribution and molecular function. Interestingly, a large proportion of proteins (38%) were from cellular membranes and we were able to characterize numerous proteins involved in cancer initiation and progression such as the tumor suppressor p53 and the epidermal growth factor receptor. Together, this study represents the largest proteome database of breast cancer cells realized to date and demonstrates the value of using Orbitrap MS for deeper proteome analysis. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOI 10.1002/prca.200800083
Citations Scopus - 8
2009 Lagadec C, Meignan S, Adriaenssens E, Foveau B, Vanhecke E, Romon R, et al., 'TrkA overexpression enhances growth and metastasis of breast cancer cells', Oncogene, 28 1960-1970 (2009) [C1]

The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors p... [more]

The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy. © 2009 Macmillan Publishers Limited All rights reserved.

DOI 10.1038/onc.2009.61
Citations Scopus - 95
2008 Hondermarck H, Tastet C, Yazidi-Belkoura IE, Toillon RA, Bourhis XL, 'Proteomics of breast cancer: The quest for markers and therapeutic targets', Journal of Proteome Research, 7 1403-1411 (2008) [C1]

Proteomics of breast cancer has already delivered significant data in terms of proteome profiling in addition to the identification of a few proteins of potential interest for dia... [more]

Proteomics of breast cancer has already delivered significant data in terms of proteome profiling in addition to the identification of a few proteins of potential interest for diagnosis and treatment. With more pathological and experimental situations being studied, it now enters into a new phase dominated by the concepts of deep proteome analysis and the definition of protein-protein interaction networks leading to mammary cell deregulation and cancer progression. Together, what could be called "Systems Proteomics", integrating with information from the genomics and the physiopathology, is clearly emerging to become the frame for future investigations. However, difficulties ahead should not be underestimated. First, the proteome is complex, and current tools are still far from providing a definitive solution for its exploration. Second, breast cancer is a multifactorial disease which is so diverse that a great deal of time and efforts will be necessary to define its associated proteome modifications and translate it into practical applications for the clinic. © 2008 American Chemical Society.

DOI 10.1021/pr700870c
Citations Scopus - 39
2008 Hondermarck H, 'Nerve growth factor: The dark side of the icon', American Journal of Pathology, 172 865-867 (2008) [C3]
DOI 10.2353/ajpath.2008.080008
Citations Scopus - 2
2008 Lagadec C, Adriaenssens E, Toillon RA, Chopin V, Romon R, Van Coppenolle F, et al., 'Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells', Oncogene, 27 1472-1477 (2008)

Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-relate... [more]

Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-a (ER-a)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-a status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-a-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-a status. © 2008 Nature Publishing Group All rights reserved.

DOI 10.1038/sj.onc.1210749
Citations Scopus - 29
2008 Adriaenssens E, Vanhecke E, Saule P, Mougel A, Page A, Romon R, et al., 'Nerve growth factor is a potential therapeutic target in breast cancer', Cancer Research, 68 346-351 (2008) [C1]

We show here that nerve growth factor (NGF), the prototypic neurotrophin, can be targeted in breast cancer to inhibit tumor cell proliferation, survival, and metastasis. Analysis ... [more]

We show here that nerve growth factor (NGF), the prototypic neurotrophin, can be targeted in breast cancer to inhibit tumor cell proliferation, survival, and metastasis. Analysis of a series of biopsies revealed widespread expression of NGF in the majority of human breast tumors, with anti-NGF immunoreactivity concentrated in the epithelial cancer cells. Moreover, immunodeficient mice xenografted with human breast cancer cells and treated with either anti-NGF antibodies or small interfering RNA against NGF displayed inhibited tumor growth and metastasis. Such treatments directed against NGF induced a decrease in cell proliferation with a concomitant increase in apoptosis of breast cancer cells and an inhibition of tumor angiogenesis. Together, these data indicate that targeting NGF in breast cancer may have therapeutic ramifications. ©2008 American Association for Cancer Research.

DOI 10.1158/0008-5472.CAN-07-1183
Citations Scopus - 93
2008 Berteaux N, Aptel N, Cathala G, Genton C, Coll J, Daccache A, et al., 'A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression', Molecular and Cellular Biology, 28 6731-6745 (2008) [C1]

The H19/IGFf2 locus belongs to a large imprinted domain located on human chromosome 11p15.5 (homologue to mouse distal chromosome 7). The H19 gene is expressed from the maternal a... [more]

The H19/IGFf2 locus belongs to a large imprinted domain located on human chromosome 11p15.5 (homologue to mouse distal chromosome 7). The H19 gene is expressed from the maternal allele, while IGF2 is paternally expressed. Natural antisense transcripts and intergenic transcription have been involved in many aspects of eukaryotic gene expression, including genomic imprinting and RNA interference. However, apart from the identification of some IGF2 antisense transcripts, few data are available on that topic at the H19/IGF2 locus. We identify here a novel transcriptional activity at both the human and the mouse H19/IGF2 imprinted loci. This activity occurs antisense to the H19 gene and has the potential to produce a single 120-kb transcript that we called the 91H RNA. This nuclear and short-lived RNA is not imprinted in mouse but is expressed predominantly from the maternal allele in both mice and humans within the H19 gene region. Moreover, the transcript is stabilized in breast cancer cells and overexpressed in human breast tumors. Finally, knockdown experiments showed that, in humans, 91H, rather than affecting H19 expression, regulates IGF2 expression in trans. Copyright © 2008, American Society for Microbiology. All Rights Reserved.

DOI 10.1128/MCB.02103-07
Citations Scopus - 76
2007 Com E, Hondermarck H, 'Functional proteomics in oncology: To understand more than to describe', Medecine/Sciences, 23 27-30 (2007)

Like other -omics, proteomics is traditionally understood as a method that allows a global description of molecular content (here proteins) of a biological sample, used to identif... [more]

Like other -omics, proteomics is traditionally understood as a method that allows a global description of molecular content (here proteins) of a biological sample, used to identify new biomarkers in diseases such as cancers. Proteomics is also a powerful tool to identify the molecular mechanisms of diseases. In cancer, deregulation of cell growth and migration is related to alterations in cell signalling and the numerous alterations in protein-protein and protein-nucleic acid interactions that account for the malignant phenotype are only partly understood. Based on its capacity to separate and identify proteins, including those with post-translational modifications, proteomics provides new ways to understand post-genomic events that contribute to transformation and to identify new therapeutic targets.

Citations Scopus - 4
2007 Vandermoere F, El Yazidi-Belkoura I, Demon Y, Slomianny C, Antol J, Lemoine J, Hondermarck H, 'Proteomics exploration reveals that actin is a signaling target of the kinase Akt', Molecular and Cellular Proteomics, 6 114-124 (2007)

The serine/threonine kinase Akt is a key mediator of cell survival and cell growth that is activated by most growth factors, but its downstream signaling largely remains to be elu... [more]

The serine/threonine kinase Akt is a key mediator of cell survival and cell growth that is activated by most growth factors, but its downstream signaling largely remains to be elucidated. To identify signaling partners of Akt, we analyzed proteins co-immunoprecipitated with Akt in MCF-7 breast cancer cells. Mass spectrometry analysis (MALDI-TOF and MS-MS) of SIDS-PAGE-separated Akt co-immunoprecipitates allowed the identification of 10 proteins: a-actinin, valosin-containing protein, inhibitor ¿B kinase, mortalin, tubulin ß, cytokeratin 8, actin, 14-3-3d, proliferating cell nuclear antigen, and heat shock protein HSP27. The identification of these putative Akt binding partners were validated with specific antibodies. Interestingly, the major protein band observed in Akt co-immunoprecipitates was found to be the cytoskeleton protein actin for which a 14-fold increase was observed in Akt-activated compared with non-activated conditions. The interaction between Akt and actin was further confirmed by reverse immunoprecipitation, and confocal microscopy demonstrated a co-localization specifically induced under growth factor stimulation. The use of wortmannin indicated a dependence on the phosphatidylinositol 3-kinase pathway. Using a p hospho-Akt substrate antibody, the phosphorylation of actin on an Akt consensus site was detected upon growth factor stimulation, both in cellulo and in vitro, suggesting that actin is a substrate of Akt kinase activity. Interestingly, cortical remodeling of actin associated with cell migration was reversed by small interfering RNA directed against Akt, indicating the involvement of Akt in the dynamic reorganization of actin cytoskeleton germane to breast cancer cell migration. Together these data identify actin as a new functional target of AM signaling. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/mcp.M600335-MCP200
Citations Scopus - 73
2007 Toillon RA, Lagadec C, Page A, Chopin V, Sautière PE, Ricort JM, et al., 'Proteomics demonstration that normal breast epithelial cells can induce apoptosis of breast cancer cells through insulin-like growth factor-binding protein-3 and maspin', Molecular and Cellular Proteomics, 6 1239-1247 (2007)

Normal breast epithelial cells are known to exert an apoptotic effect on breast cancer cells, resulting in a potential paracrine inhibition of breast tumor development. In this st... [more]

Normal breast epithelial cells are known to exert an apoptotic effect on breast cancer cells, resulting in a potential paracrine inhibition of breast tumor development. In this study we purified and characterized the apoptosis-inducing factors secreted by normal breast epithelial cells. Conditioned medium was concentrated by ultrafiltration and separated on reverse phase Sep-Pak C 18 and HPLC. The proapoptotic activity of eluted fractions was tested on MCF-7 breast cancer cells, and nano-LC-nano-ESI-MS/MS allowed the identification of insulin-like growth factor-binding protein-3 (IGFBP-3) and maspin as the pro-apoptotic factors produced by normal breast epithelial cells. Western blot analysis of conditioned media confirmed the specific secretion of IGFBP-3 and maspin by normal cells but not by breast cancer cells. Immunodepletion of IGFBP-3 and maspin completely abolished the normal cell-induced apoptosis of cancer cells, and re-combinant proteins reproduced the effect of normal cell-conditioned medium on apoptosis of breast cancer cells. Together our results indicated that normal breast epithelial cells can induce apoptosis of breast cancer cells through IGFBP-3 and maspin. These findings provide a molecular hypothesis for the long observed inhibitory effect of ormal surrounding cells on breast cancer development. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/mcp.M600477-MCP200
Citations Scopus - 21
2007 Com E, Lagadec C, Page A, El Yazidi-Belkoura I, Siomianny C, Spencer A, et al., 'Nerve growth factor receptor TrkA signaling in breast cancer cells involves Ku70 to prevent apoptosis', Molecular and Cellular Proteomics, 6 1842-1854 (2007)

The nerve growth factor (NGF)-tyrosine kinase receptor TrkA plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation, and... [more]

The nerve growth factor (NGF)-tyrosine kinase receptor TrkA plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation, and proliferation. In breast cancer cells, TrkA stimulation results in the activation of cellular growth, but downstream signaling largely remains to be described. Here we used a proteomics-based approach to identify partners involved in TrkA signaling in breast cancer cells. Wild type and modified TrkA chimeric constructs with green fluorescent protein were transfected in MCF-7 cells, and co-immunoprecipitated proteins were separated by SDS-PAGE before nano-LC-MS/MS analysis. Several TrkA putative signaling partners were identified among which was the DNA repair protein Ku70, which is increasingly reported for its role in cell survival and carcinogenesis. Physiological interaction of Ku70 with endogenous TrkA was induced upon NGF stimulation in non-transfected cells, and co-localization was observed with confocal microscopy. Mass spectrometry analysis and Western blotting of phosphotyrosine immunoprecipitates demonstrated the induction of Ku70 tyrosine phosphorylation upon NGF stimulation. Interestingly no interaction between TrkA and Ku70 was detected in PC12 cells in the absence or presence of NGF, suggesting that it is not involved in the initiation of neuronal differentiation. In breast cancer cells, RNA interference indicated that whereas Ku70 depletion had no direct effect on cell survival, it induced a strong potentiation of apoptosis in TrkA-overexpressing cells. In conclusion, TrkA signaling appears to be proapoptotic in the absence of Ku70, and this protein might therefore play a role in the long time reported ambivalence of tyrosine kinase receptors that can exhibit both anti- and eventually proapoptotic activities. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/mcp.M700119-MCP200
Citations Scopus - 28
2006 Vandermoere F, El Yazidi-Belkoura I, Slomianny C, Demont Y, Bidaux G, Adriaenssens E, et al., 'The Valosin-containing Protein (VCP) is a target of Akt signaling required for cell survival', Journal of Biological Chemistry, 281 14307-14313 (2006)

The serine/threonine kinase Akt is a key mediator of cell survival and growth, but its precise mechanism of action, and more specifically, the nature of its signaling partners lar... [more]

The serine/threonine kinase Akt is a key mediator of cell survival and growth, but its precise mechanism of action, and more specifically, the nature of its signaling partners largely remain to be elucidated. We show, using a proteomics-based approach, that the valosin-containing protein (VCP), a member of the AAA (ATPases associated with a variety of cellular activities) family, is a target of Akt signaling. SDS-PAGE of Akt co-immunoprecipitated proteins obtained from MCF-7 breast cancer cells revealed the increase of a 97-kDa band under Akt activation. Mass spectrometry analysis allowed the identification of VCP, and we have shown a serine/threonine phosphorylation on an Akt consensus site upon activation by growth factors. Site-directed mutagenesis identified Ser-351, Ser-745, and Ser-747 as Akt phosphorylation sites on VCP. Confocal microscopy indicated a co-localization between Akt and VCP upon Akt stimulation. Interestingly, small interfering RNA against VCP induced an inhibition of the growth factor-induced activation of NF-¿B and a potent pro-apoptotic effect. Together, these data identify VCP as an essential target of Akt signaling. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/jbc.M510003200
Citations Scopus - 62
2006 Hondermarck H, 'Proteomics and¿breast cancer: new perspectives and¿limitations', Pathologie Biologie, 54 194-198 (2006)

From differential analysis for the identification of biomarkers, to functional analysis for the evidencing of new therapeutic targets, proteomics brings new comprehensive informat... [more]

From differential analysis for the identification of biomarkers, to functional analysis for the evidencing of new therapeutic targets, proteomics brings new comprehensive information for a better understanding of the molecular basis of oncology and new perspectives for the clinic. However the major limitation of proteomic investigations and more generally of post-genomic approaches remains the molecular and cellular complexity of biological systems. This will be illustrated with the case of breast cancer. © 2006 Elsevier SAS. All rights reserved.

DOI 10.1016/j.patbio.2006.02.001
Citations Scopus - 2
2005 Berteaux N, Lottin S, Monté D, Pinte S, Quatannens B, Coll J, et al., 'H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1', Journal of Biological Chemistry, 280 29625-29636 (2005)

The imprinted H19 gene has riboregulatory functions. We show here that H19 transcription is up-regulated during the S-phase of growth-stimulated cells and that the H19 promoter is... [more]

The imprinted H19 gene has riboregulatory functions. We show here that H19 transcription is up-regulated during the S-phase of growth-stimulated cells and that the H19 promoter is activated by E2F1 in breast cancer cells. H19 repression by pRb and E2F6 confirms the E2F1-dependent control of the H19 promoter. Consistently, we demonstrate by chromatin immunoprecipitation assays that endogenous E2F1 is recruited to the H19 promoter in vivo. The functionality of E2F promoter sites was further confirmed by gel shift and mutagenesis experiments, revealing that these sites are required for binding and promoter response to E2F1 exogenous expression and serum stimulation. Furthermore, we show that H19 overexpression confers a growth advantage on breast cancer cells released from growth arrest as well as in asynchronously growing cells. The H19 knockdown by small interfering RNA duplexes impedes S-phase entry in both wild-type and stably H19-transfected cells. Based on these findings, we conclude that the H19 RNA is actively linked to E2F1 to promote cell cycle progression of breast cancer cells. This clearly supports the H19 oncogenic function in breast tumor genesis. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI 10.1074/jbc.M504033200
Citations Scopus - 153
2005 Dollé L, Oliveira MJ, Bruyneel E, Hondermarck H, Bracke M, 'Nerve Growth Factor mediates its pro-invasive effect in parallel with the release of a soluble E-cadherin fragment from breast cancer MCF-7/AZ cells', Journal of Dairy Research, 72 20-26 (2005)

To define better the function of Nerve Growth Factor (NGF) in breast cancer progression, we investigated whether this polypeptide was able to induce breast cancer cell invasion. N... [more]

To define better the function of Nerve Growth Factor (NGF) in breast cancer progression, we investigated whether this polypeptide was able to induce breast cancer cell invasion. NGF inhibited aggregation of tumour cells through modulation of the E-cadherin/catenin complex function. In addition, NGF induced the breast cancer cells to invade into Matrigel. We focused our attention on how NGF prevents aggregation, in order to discover the signalling pathway that leads tumour cells to acquire the invasive phenotype. Moreover, studies on the identification of signalling pathways that are responsive for NGF-induced invasion will be basically described. © Proprietors of Journal of Dairy Research 2005.

DOI 10.1017/S0022029905001160
Citations Scopus - 11
2005 Vandermoere F, Yazidi-Belkoura IE, Adriaenssens E, Lemoine J, Hondermarck H, 'The antiapoptotic effect of fibroblast growth factor-2 is mediated through nuclear factor-¿B activation induced via interaction between Akt and I¿B kinase-ß in breast cancer cells', Oncogene, 24 5482-5491 (2005)

Fibroblast growth factor-2 (FGF-2) is known for its mitogenic and motogenic effects on breast cancer cells. Here, we demonstrate that FGF-2 is also a potent stimulator of breast c... [more]

Fibroblast growth factor-2 (FGF-2) is known for its mitogenic and motogenic effects on breast cancer cells. Here, we demonstrate that FGF-2 is also a potent stimulator of breast cancer cell survival, as it counteracts the apoptotic activity of the C2 ceramide analogue and various chemotherapeutic agents (5-fluorouracil, camptothecin, etoposide) in MCF-7, T47-D and BT-20 cells. The use of pharmacological inhibitors (PD98059, wortmannin, LY294002, SN50) and rransfection with negative dominants (I¿Bm, p110(PI3K (phosphoinositide 3-kinase))*¿K, AktND) or small interfering RNA targeted against Akt indicated that PI3K/Akt and nuclear factor-¿B (NF-¿B), but not p42/p44 MAP-kinases, were required to stimulate FGF-2 antiapoptotic activity. The activation of NF-¿B was dependent on PI3K/Akt, and using a combination of approaches based on immunoprecipitation, Western blotting and proteomics (two-dimensional electrophoresis and mass spectrometry), we identified the beta form of I¿B kinase (IKKß) as a target of Akt signaling. The selective disruption of IKKß using small interfering RNA induced a potent inhibition of Akt-mediated activation of NF-¿B and cell survival, indicating the functional involvement of IKKß in FGF-2 antiapoptotic signaling. Together, these results demonstrate Akt/IKKß interaction in NF-¿B pathways, thereby emphasizing the potential of these proteins as therapeutic targets in breast cancer. © 2005 Nature Publishing Group All rights reserved.

DOI 10.1038/sj.onc.1208713
Citations Scopus - 70
2004 Chopin V, Slomianny C, Hondermarck H, Le Bourhis X, 'Synergistic induction of apoptosis in breast cancer cells by cotreatment with butyrate and TNF-alpha, TRAIL, or anti-Fas agonist antibody involves enhancement of death receptors' signaling and requires P21

Inhibitors of histone deacetylase (HDAC) are considered as potential anticancer agents. We have previously demonstrated that an inhibitor of HDAC, sodium butyrate (NaB), induces a... [more]

Inhibitors of histone deacetylase (HDAC) are considered as potential anticancer agents. We have previously demonstrated that an inhibitor of HDAC, sodium butyrate (NaB), induces apoptosis of breast cancer cells in a P53-independent and P21 waf1 -dependent manner. In this study, we showed that tumor necrosis factor-alpha (TNF-alpha), TNF-related apoptosis-inducing ligand (TRAIL), and anti-Fas agonist antibody potentiated NaB-induced growth inhibition through synergistic induction of apoptosis in breast cancer cell lines (MCF-7, T47-D, and BT-20). In MCF-7 cells, NaB increased the expression of death receptors; NaB alone or in combination with TNF-alpha, TRAIL, and anti-Fas agonist antibody increased the levels of Bid, tBid, and that of cytosolic cytochrome c. Synergistic induction of apoptosis was strongly inhibited by dominant-negative Fas-associated death domain (FADD) and inhibitors of caspases-8 and -9, indicating that potentiation of apoptosis involved key elements of death receptors' signaling pathways. Moreover, cotreatment of NaB and ligands of death receptors up-regulated the levels of P21 waf1 and that of proliferating cell nuclear antigen (PCNA) associated with P21 waf1 . Transient transfections of p21 waf1 antisense or p21 waf1 deficient for its interaction with PCNA abolished synergistic induction of apoptosis. This suggested that potentiation of apoptosis by cotreatments required P21 waf1 and its interaction with PCNA. Since breast tumors contain rarely p21 mutations, our results may open interesting prospects in the fight against breast cancer. © 2004 Elsevier Inc. All rights reserved.

DOI 10.1016/j.yexcr.2004.04.038
Citations Scopus - 74
2004 Dollé L, Adriaenssens E, El Yazidi-Belkoura I, Le Bourhis X, Nurcombe V, Hondermarck H, 'Nerve growth factor receptors and signaling in breast cancer', Current Cancer Drug Targets, 4 463-470 (2004)

Nerve growth factor (NGF) has long been known for its effects on neuronal cell survival and differentiation. This prototypical neurotrophic factor stimulates neurons through two d... [more]

Nerve growth factor (NGF) has long been known for its effects on neuronal cell survival and differentiation. This prototypical neurotrophic factor stimulates neurons through two distinct classes of membrane receptors: the TrkA tyrosine kinase receptor, and the tumor necrosis factor receptor family member p75 NTR , also known as the common neurotrophin receptor. Somewhat surprisingly, there is a growing body of evidence indicating that NGF is also a major stimulator of breast cancer cell growth. Both the survival and proliferation of breast cancer cells are strongly stimulated by NGF, mediated by TrkA and p75 NTR respectively, utilising signaling pathways similar to those described for neurons. In addition, although NGF is produced by breast cancer cells, it is not in normal breast epithelial cells, giving rise to an autocrine stimulation of tumor growth. Therefore, NGF receptors and signaling are thus looking increasingly promising as potential drug targets for breast cancer.

DOI 10.2174/1568009043332853
Citations Scopus - 61
2003 El Yazidi-Belkoura I, Adriaenssens E, Dollé L, Descamps S, Hondermarck H, 'Tumor necrosis factor receptor-associated death domain protein is involved in the neurotrophin receptor-mediated antiapoptotic activity of nerve growth factor in breast cancer cells', Journal of Biological Chemistry, 278 16952-16956 (2003)

The common neurotrophin receptor p75 NTR has been shown to initiate intracellular signaling that leads either to cell survival or to apoptosis depending on the cell type examined... [more]

The common neurotrophin receptor p75 NTR has been shown to initiate intracellular signaling that leads either to cell survival or to apoptosis depending on the cell type examined; however, the mechanism by which p75 NTR initiates its intracellular transduction remains unclear. We show here that the tumor necrosis factor receptor-associated death domain protein (TRADD) interacts with p75 NTR upon nerve growth factor (NGF) stimulation. TRADD could be immunodetected after p75 NTR immunoprecipitation from MCF-7 breast cancer cells stimulated by nerve growth factor. In addition, confocal microscopy indicated that NGF stimulation induced the plasma membrane localization of TRADD. Using a dominant negative form of TRADD, we also show that interactions between p75 NTR and TRADD are dependent on the death domain of TRADD, thus demonstrating its requirement for binding. Furthermore, the p75 NTR -mediated activation of NF-¿B was inhibited by transfection with a dominant negative TRADD, resulting in an inhibition of NGF antiapoptotic activity. These results thus demonstrate that TRADD is involved in the p75 NTR -mediated antiapoptotic activity of NGF in breast cancer cells.

DOI 10.1074/jbc.M300631200
Citations Scopus - 51
2003 Dollé L, El Yazidi-Belkoura I, Adriaenssens E, Nurcombe V, Hondermarck H, 'Nerve growth factor overexpression and autocrine loop in breast cancer cells', Oncogene, 22 5592-5601 (2003)

We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were ... [more]

We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were detected in breast cancer cells by reverse transcription-PCR, Western blotting, ELISA assay and immunohistochemistry. Conversely, NGF production could not be detected in normal breast epithelial cells at either the transcriptional or protein level. Confocal analysis indicated the presence of NGF within classical secretion vesicles. Breast cancer cell-produced NGF was biologically active, as demonstrated by its ability to induce the neuronal differentiation of embryonic neural precursor cells. Importantly, the constitutive growth of breast cancer cells was strongly inhibited by either NGF-neutralizing antibodies or K-252a, a pharmacological inhibitor of NGF receptor TrkA, indicating the existence of an NGF autocrine loop. Together, our data demonstrate the physiological relevance of NGF in breast cancer and its potential interest as a marker and therapeutic target.

DOI 10.1038/sj.onc.1206805
Citations Scopus - 88
2003 Hondermarck H, 'Breast cancer: when proteomics challenges biological complexity.', Molecular &amp; cellular proteomics : MCP., 2 281-291 (2003)

Proteomics is now entering into the field of biomedicine with declared hopes for the identification of new pathological markers and therapeutic targets. Current proteomic tools al... [more]

Proteomics is now entering into the field of biomedicine with declared hopes for the identification of new pathological markers and therapeutic targets. Current proteomic tools allow large-scale, high-throughput analyses for the detection, identification, and functional investigation of low-abundant proteins. However, the major limitation of proteomic investigations remains the complexity of biological structures and physiological processes, rendering the path of exploration of related pathologies paved with various difficulties and pitfalls. The case of breast cancer illustrates the major challenge facing modern proteomics and more generally post-genomics: to tackle the complexity of life.

Citations Scopus - 64
2002 Adriaenssens E, Lemoine J, El Yazidi-Belkoura I, Hondermarck H, 'Growth signaling in breast cancer cells: Outcomes and promises of proteomics', Biochemical Pharmacology, 64 797-803 (2002)

Methods in functional proteomics are now used to study the intracellular signaling pathways that underlie the development of breast cancer. As shown with fibroblast growth factor-... [more]

Methods in functional proteomics are now used to study the intracellular signaling pathways that underlie the development of breast cancer. As shown with fibroblast growth factor-2, the oncogenic/non-coding mRNA H19 and 14-3-3 proteins, proteomics is a powerful approach to identify signaling proteins and to decipher the complex signaling circuitry involved in growth of breast cancer cells. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast cancerogenesis and to identify new therapeutic targets. © 2002 Elsevier Science Inc. All rights reserved.

DOI 10.1016/S0006-2952(02)01141-3
Citations Scopus - 18
2002 Adriaenssens E, Lottin S, Berteaux N, Hornez L, Fauquette W, Fafeur V, et al., 'Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells', Experimental Cell Research, 275 215-229 (2002)

The H19 gene is an imprinted gene expressed from the maternal allele. It is known to function as an RNA molecule. We previously reported that in breast adenocarcinoma, H19 is ofte... [more]

The H19 gene is an imprinted gene expressed from the maternal allele. It is known to function as an RNA molecule. We previously reported that in breast adenocarcinoma, H19 is often overexpressed in stromal cells and preferentially located at the epithelium/stroma boundary, suggesting that epithelial/mesenchymal interactions can control H19 RNA expression. In some cases of breast adenocarcinoma with poor prognosis, H19 is overexpressed in epithelial cells. Therefore we examined whether mesenchymal factors can induce H19 expression in epithelial cells. Using quantitative RT-PCR and in situ hybridization, we found that when mammary epithelial cells were cultured in collagen gels, H19 expression was strongly up-regulated compared to when cells were cultured on plastic. Collagen gels allow three-dimensional growth of epithelial cells and morphogenetic responses to soluble factors. A conditioned medium from MRC-5 fibroblasts caused branching morphogenesis of HBL-100 cells and invasive growth of MDA-MB-231 cells, whereas MCF-7 cells were unresponsive. Induction of H19 expression correlated with morphological changes in HBL-100 and in MDA-MB-231 cells, whereas H19 expression was not induced in MCF-7 cells. Using a blocking antibody, HGF/SF was identified as the fibroblast-derived growth factor capable of inducing H19 expression and cell morphogenesis. We further demonstrated that H19 promoter activity was stimulated by various growth factors using transient transfection in MDCK epithelial cells. HGF/SF was more efficient than EGF or FGF-2 in transactivating the H19 promoter, whereas IGF-2, TGFß-1, and TNF-a were ineffective. This activation by HGF/SF was prevented by pharmacological inhibition of MAP kinase or of phospholipase C. We conclude that H19 is a target gene for HGF/SF, a known regulator of epithelial/mesenchymal interactions, and suggest that the up-regulation of H19 may be implicated in morphogenesis and/or migration of epithelial cells. © 2002 Elsevier Science (USA).

DOI 10.1006/excr.2002.5500
Citations Scopus - 27
2002 Vergote D, Cren-Olivé C, Chopin V, Toillon RA, Rolando C, Hondermarck H, Bourhis XL, '(-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts', Breast Cancer Research and Treatment, 76 195-201 (2002)

(-)-Epigallocatechin (EGC), one of green tea polyphenols, has been shown to inhibit growth of cancer cells. However its mechanism of action is poorly known. We show here that EGC ... [more]

(-)-Epigallocatechin (EGC), one of green tea polyphenols, has been shown to inhibit growth of cancer cells. However its mechanism of action is poorly known. We show here that EGC strongly inhibited the growth of breast cancer cell lines (MCF-7 and MDA-MB-231) but not that of normal breast epithelial cells. The inhibition of breast cancer cell growth was due to an induction of apoptosis, without any change in cell cycle progression. MCF-7 cells are known to express a wild-type p53 whereas MDA-MB-231 cells express a mutated p53. The fact that EGC induced apoptosis in both these cell lines suggests that the EGC-triggered apoptosis is independent of p53 status. Moreover, neutralizing antibodies against the death receptor Fas and inhibitors of caspases, such as caspase-8 and -10, efficiently inhibited the EGC-triggered apoptosis. In addition, immunoblotting revealed that EGC treatment was correlated with a decrease in Bcl-2 and an increase in Bax level. These results suggest that EGC-triggered apoptosis in breast cancer cells requires Fas signaling.

DOI 10.1023/A:1020833410523
Citations Scopus - 77
2002 Hondermarck H, 'Proteomics of breast cancer', Biofutur, 43-47 (2002)
2002 Lottin S, Vercoutter-Edouart AS, Adriaenssens E, Czeszak X, Lemoine J, Roudbaraki M, et al., 'Thioredoxin post-transcriptional regulation by H19 provides a new function to mRNA-like non-coding RNA', Oncogene, 21 1625-1631 (2002)

Classically, the functional product of coding genes is a protein whose synthesis is directed by an mRNA-template. However, in the last few years several genes yielding an mRNA-lik... [more]

Classically, the functional product of coding genes is a protein whose synthesis is directed by an mRNA-template. However, in the last few years several genes yielding an mRNA-like non-coding RNA as a functional product have been identified. In most cases these transcripts are synthesized by the RNA polymerase II, capped, spliced and polyadenylated, like classical mRNA. These latter have non-conserved open reading frames and seem to be untranslated. Consequently, it has been proposed and admitted that these genes act at the RNA level, and are so-called 'riboregulators'. H19 belongs to this class of gene and its role remains a matter of debate: for some authors it is an oncogene, for others a tumour suppressor. Here, we demonstrate, using a proteomic approach, that an H19 overexpression in human cancerous mammary epithelial cells stably transfected with genomic DNA containing the entire H19 gene is responsible for positively regulating at the post-tra nscriptional level the thioredoxin, a key protein of the cellular redox metabolism. Interestingly, this protein accumulates in many cancerous tissues, such as breast carcinomas in which we have also demonstrated an overexpression of the H19 gene.

DOI 10.1038/sj/onc/1205233
Citations Scopus - 36
2002 Jiang ZW, Lebourhis-Xuefen, Hondermarck H, 'Progressing growth of tumor cell and synthesis of Bip/GRP78', Chinese Pharmacological Bulletin, 18 79-83 (2002)

AIM: To explore the relationship between tumor progressing growth and synthesis of Bip/GRP78 in vitro. METHOD: Using tumor cell culture, ion exchange chromatography, SDS-PAGE, spe... [more]

AIM: To explore the relationship between tumor progressing growth and synthesis of Bip/GRP78 in vitro. METHOD: Using tumor cell culture, ion exchange chromatography, SDS-PAGE, specific enzymatic, chemical catalysis, mass spectra and so on, the synthesis of Bip/GRP78 of cells growth in exponential, confluent and post-confluent phases was examined,and compared to normal breast epithelial cells. RESULTS: During the progressing growth, tumor cells' synthesis of Bip/GRP78 exhibited growth situation, cell density and malignant degree-dependent. CONCLUSIONS: During the progressing growth, tumor cells can maintain its homeostasis by synthesizing Bip/GRP78. This synthesis is intensely growth situation. Cell density and malignant degree-dependent. By this synthesis, tumor cell establishs its defensive system. Because increasing investigate results have shown that Bip/GRP78 can decrease the sensitivity of tumor cell to be killed by cytotoxic T lymphocytes, increase its tumorigencity and prevent its apoptosis. So aiming at destruction of the synthesis of Bip/GRP78 may point to a new approaches to the therapy of cancer.

Citations Scopus - 3
2002 Hondermarck H, Dollé L, Yazidi-Belkoura IE, Vercoutter-Edouart AS, Adriaenssens E, Lemoine J, 'Functional proteomics of breast cancer for signal pathway profiling and target discovery', Journal of Mammary Gland Biology and Neoplasia, 7 395-405 (2002)

The near completion of human genome sequencing and the introduction of mass spectrometry combined with advanced bioinformatics for protein identification have led to the emergence... [more]

The near completion of human genome sequencing and the introduction of mass spectrometry combined with advanced bioinformatics for protein identification have led to the emergence of proteomics as a powerful tool for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified proteins of potential clinical interest, such as the molecular chaperone 14-3-3 sigma and the heat shock protein HSP90, and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer cells. As illustrated by fibroblast growth factor-2 and the H19 noncoding oncogenic mRNA, proteomics is a pertinent approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth and metastasis. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast carcinogenesis and to identify new therapeutic targets. The next challenge will be the introduction of proteomics as a tool for the clinic, for the establishment of diagnosis, prognosis, and the monitoring of treatment; however, this ambitious goal still requires further technological progress in the field.

DOI 10.1023/A:1024086015542
Citations Scopus - 18
2002 El Yazidi-Belkoura I, Adriaenssens E, Vercoutter-Edouart AS, Lemoine J, Nurcombe V, Hondermarck H, 'Proteomics of breast cancer: Outcomes and prospects', Technology in Cancer Research and Treatment, 1 287-295 (2002)

Breast cancer is a major public health problem. The identification of new markers to differentiate neoplastic from the normal cells, more thorough understanding of different stage... [more]

Breast cancer is a major public health problem. The identification of new markers to differentiate neoplastic from the normal cells, more thorough understanding of different stages of the pathology, as well as the definition of new therapeutic targets, are all of critical importance. With the completion of human genome sequencing and the introduction of mass spectrometry, combined with protein identification via advanced bioinformatics, proteomics has emerged as a valuable tool for the discovery of new molecular markers. New methods in functional proteomics have also been developed to study the intracellular signaling pathways that underline the development of breast cancer. As illustrated with the examples of fibroblast growth factor-2 and H19, an oncogenic, noncoding mRNA, proteomics have become a powerful approach for deciphering the complex signaling circuitry involved in tumor growth. Breast cancer proteomics have already identified proteins of potential clinical interest (such as the molecular chaperone 14-3-3 sigma) and technological innovations in large scale/high throughput analysis are now ushering in new prospects.

Citations Scopus - 14
2001 Vercoutter-Édouart AS, Peyrat JP, Lemoine J, Hondermarck H, 'Proteomic analysis: Why and how?', Bulletin du Cancer, 88 663-670 (2001)

The proteome, first formalized in 1995, designs all the proteins expressed by the genome of a cell, tissu, or organ at a defined time. Proteomic analysis leads to a description of... [more]

The proteome, first formalized in 1995, designs all the proteins expressed by the genome of a cell, tissu, or organ at a defined time. Proteomic analysis leads to a description of the regulation (gene expression by the study of proteins and of their post-translational modifications. Proteomic analysis is based on three technologies: 1) Two-dimensional electrophoresis allowing the separation of thousands of proteins from a single mixture; 2) mass spectrometry allowing the characterization of picoquantities of polypeptides and providing data on post-translational modifications; 3) Bioinformatic which is required for the quantification of protein level and for the constitution of databases of protein expression profiles. Complementing the methods of the genomics, the use of proteomic analysis is widely spreading in the fields of fundamental biology, biomedicine and pharmacology for the identification of new biological markers and therapeutic targets.

Citations Scopus - 1
2001 Vercoutter-Edouart AS, Lemoine J, Bourhis XL, Louis H, Boilly B, Nurcombe V, et al., 'Proteomic analysis reveals that 14-3-3s is down-regulated in human breast cancer cells', Cancer Research, 61 76-80 (2001)

The class of molecular chaperones known as 14-3-3 is involved in the control of cellular growth by virtue of its apparent regulation of various signaling pathways, including the R... [more]

The class of molecular chaperones known as 14-3-3 is involved in the control of cellular growth by virtue of its apparent regulation of various signaling pathways, including the Raf/mitogen-activated protein kinase pathway. In breast cancer cells, the s form of 14-3-3 has been shown to interact with cyclin-dependent kinases and to control the rate of entry into mitosis. To test for a direct role for 14-3-3 in breast epithelial cell neoplasia, we have quantitated 14-3-3 protein levels using a proteomic approach based on two-dimensional electrophoresis and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF). We show here that 14-3-3s protein is strongly down-regulated in the prototypic breast cancer cell lines MCF-7 and MDA-MB-231 and in primary breast carcinomas as compared with normal breast epithelial cells. In contrast, levels of the a, ß, d, or ¿ isoforms of 14-3-3 were the same in both normal and transformed cells. The data support the idea that 14-3-3s is involved in the neoplastic transition of breast epithelial cells by virtue of its role as a tumor suppressor; as such, it may constitute a robust marker with clinical efficacy for this pathology.

Citations Scopus - 153
2001 Descamp S, Pawlowski V, Révillion F, Hornez L, Hebbar M, Boilly B, et al., 'Expression of nerve growth factor receptors and their prognostic value in human breast cancer', Cancer Research, 61 4337-4340 (2001)

Nerve growth factor (NGF) has been shown recently to be mitogenic for human breast cancer cells. In the present study, we have assayed the expression of NGF receptors (NGFRs: TrkA... [more]

Nerve growth factor (NGF) has been shown recently to be mitogenic for human breast cancer cells. In the present study, we have assayed the expression of NGF receptors (NGFRs: TrkA and p75) mRNAs in 363 human primary breast cancers, using real-time quantitative reverse transcription-PCR. NGFRs were found in all of the tumor biopsies. TrkA and p75 were positively correlated and were respectively associated with the histoprognostic grading and the tumor type. NGFRs were both related to progesterone receptors. In univariate analyses, TrkA ( > upper quartile) was associated with longer overall survival. Histoprognostic grading, tumor size, node involvement, and steroid receptors were also prognostic factors. In Cox multivariate analyses, TrkA was not a prognostic parameter. This study demonstrates the expression of NGFRs in breast cancer and points out that patients with high levels of TrkA have a more favorable overall survival prognosis.

Citations Scopus - 79
2001 Vercoutter-Edouart AS, Czeszak X, Crépin M, Lemoine J, Boilly B, Le Bourhis X, et al., 'Proteomic detection of changes in protein synthesis induced by fibroblast growth factor-2 in MCF-7 human breast cancer cells', Experimental Cell Research, 262 59-68 (2001)

Fibroblast growth factor-2 (FGF-2) is a potent regulator of breast cancer cell growth through stimulation of tyrosine kinase receptors and activation of the mitogen-activated prot... [more]

Fibroblast growth factor-2 (FGF-2) is a potent regulator of breast cancer cell growth through stimulation of tyrosine kinase receptors and activation of the mitogen-activated protein kinase cascade. In the present study, we have investigated changes in protein synthesis induced by FGF-2 stimulation of the prototypic human breast cancer cell line MCF-7. Using high-resolution two-dimensional electrophoresis of 35 S amino acid metabolically labeled proteins and computerized analysis of 2D autoradiograms, we found that four proteins were up-regulated within the first 12 h of FGF-2 stimulation. Mass spectrometry analysis (MALDI-TOF and MS-MS) of tryptic fragments and database searches allowed the identification of these FGF-2-regulated proteins as the heat shock proteins HSP90 and HSP70, the proliferating cel l nuclear antigen (PCNA), and the transcriptionaly controlled tumor protein (TCTP). We then analyzed the distribution of these proteins in various cancerous and normal breast epithelial cells. Interestingly, the four FGF-2-regulated proteins were found to be constitutively up-regulated in ras-transfected MCF-7 cells, indicating their relevance to the up-regulation of cellular proliferation. Moreover, HSP90 and PCNA were found at higher levels in cancerous cells than in normal cells. The role of HSP90 was further investigated using the specific inhibitor geldanamycin. We showed that the functionality of HSP90 is strictly required in order to obtain FGF-2 mitogenic stimulation in MCF-7 cells, indicating the crucial role played by this molecular chaperone in the control of breast cancer cell growth. Finally, these results show that proteomic analysis is a valuable method for identifying potential markers or therapeutic targets related to cancer growth. © 2001 Academic Press.

DOI 10.1006/excr.2000.5066
Citations Scopus - 66
2001 Descamps S, Toillon RA, Adriaenssens E, Pawlowski V, Cool SM, Nurcombe V, et al., 'Nerve Growth Factor Stimulates Proliferation and Survival of Human Breast Cancer Cells through Two Distinct Signaling Pathways', Journal of Biological Chemistry, 276 17864-17870 (2001)

We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signal... [more]

We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signaling pathway. Breast cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF receptors: p140 trkA and p75 NTR . The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of NGF on breast cancer cells required the tyrosine kinase activity of p140 trkA as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75 NTR . In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75 NTR as well as the activation of the transcription factor NF-kB, but neither p140 trkA nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75 NTR in NGF-mediated survival. Both the pharmacological NF-¿B inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptotic effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75 NTR and NF-¿B in the activation of the survival pathway in breast cancer cells.

DOI 10.1074/jbc.M010499200
Citations Scopus - 148
2001 Hondermarck H, Peyrat JP, 'Tumor typing: Proteomic analysis?', Biofutur, 43-44 (2001)
2001 Hondermarck H, Vercoutter-Edouart AS, Révillion F, Lemoine J, El-Yazidi-Belkoura I, Nurcombe V, Peyrat JP, 'Proteomics of breast cancer for marker discovery and signal pathway profiling', Proteomics, 1 1216-1232 (2001)

Breast cancer is the most common form of cancer among women and the identification of markers to discriminate tumorigenic from normal cells, as well as the different stages of thi... [more]

Breast cancer is the most common form of cancer among women and the identification of markers to discriminate tumorigenic from normal cells, as well as the different stages of this pathology, is of critical importance. Two-dimensional electrophoresis has been used before for studying breast cancer, but the progressive completion of human genomic sequencing and the introduction of mass spectrometry, combined with advanced bioinformatics for protein identification, have considerably increased the possibilities for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified markers of potential clinical interest (such as the molecular chaperone 14-3-3 sigma) and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer. As illustrated with fibroblast growth factor-2, a mitogen and motogen factor for breast cancer cells, proteomics is a powerful approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth. Together with genomics, proteomics is well on the way to molecularly characterizing the different types of breast tumor, and thus defining new therapeutic targets for future treatment.

DOI 10.1002/1615-9861(200110)1:10&amp;lt;1216::AID-PROT1216&amp;gt;3.0.CO;2-P
Citations Scopus - 106
2000 Fernig DG, Chen HL, Rahmoune H, Descamps S, Boilly B, Hondermarck H, 'Differential regulation of FGF-1 and -2 mitogenic activity is related to their kinetics of binding to heparan sulfate in MDA-MB-231 human breast cancer cells', Biochemical and Biophysical Research Communications, 267 770-776 (2000)

The growth of the malignant human mammary MDA-MB-231 cells is stimulated by fibroblast growth factor-1 (FGF-1) but not by FGF-2. When these cells are cultured in the presence of c... [more]

The growth of the malignant human mammary MDA-MB-231 cells is stimulated by fibroblast growth factor-1 (FGF-1) but not by FGF-2. When these cells are cultured in the presence of chlorate, an inhibitor of heparan sulfate (HS) sulfation, their proliferation is stimulated by both FGF-1 and FG;F-2. We analyzed the interactions of FGF-1 and FGF-2 with HS purified from the cell layer and the culture medium of control and chlorate-treated MDA-MB-231 cells. The HS from the cell layer bound FGF-1 with faster association kinetics thah the HS from the culture medium, and so had a higher affinity for FGF-1. Chlorate treatment had no significant effect on the FGF-1 binding kinetics of the HS. In contrast to FGF-1, chlorate treatment of the cells significantly altered the FGF-2 binding kinetics. The HS from untreated cells possessed two binding sites for FGF-2, one with fast association kinetics (k(ass) 470,000 to 610,000 M -1 s -1 ) and a high affinity (K(d) 46 to 70 nM) and one with slower association kinetics (k(ass) 74,000 to 100,000 M -1 s -1 ) and a lower affinity (K(d) 290 to 400 nM). HS from chloratetreated cells possessed just a single binding site for FGF-2 with fast association kinetics (k(ass) 270,000 to 290,000 M -1 s -1 ) and a high affinity (K(d) 41 to 57 nM). These results show that there is a relationship between the binding kinetics of FGFs and their ability to stimulate cell growth. (C) 2000 Academic Press.

DOI 10.1006/bbrc.1999.2028
Citations Scopus - 27
2000 Vercoutter-Edouart AS, Lemoine J, Smart CE, Nurcombe V, Boilly B, Peyrat JP, Hondermarck H, 'The mitogenic signaling pathway for fibroblast growth factor-2 involves the tyrosine phosphorylation of cyclin D2 in MCF-7 human breast cancer cells', FEBS Letters, 478 209-215 (2000)

Fibroblast growth factor-2 (FGF-2) is mitogenic for the human breast cancer cell line MCF-7; here we investigate some of the signaling pathways subserving this activity. FGF-2 sti... [more]

Fibroblast growth factor-2 (FGF-2) is mitogenic for the human breast cancer cell line MCF-7; here we investigate some of the signaling pathways subserving this activity. FGF-2 stimulation of MCF-7 cells resulted in a global increase of intracellular tyrosine phosphorylation of proteins, particularly FGF receptor substrate-2, the protooncogene product Src and the mitogen-activated protein kinase (MAP kinase) cascade. A major increase in the tyrosine phosphorylation of a 30-kDa protein species was also found. This protein was identified as cyclin D2 by mass spectrometry after trypsin digestion. Immunoprecipitation of cyclin D2 and immunoblotting with anti- phosphotyrosine antibodies confirmed that the tyrosine phosphorylation of cyclin D2 was indeed induced by FGF-2 stimulation. In addition, pharmacological inhibition of Src (with herbimycin A and PP2), and of the MAP kinase cascade (with PD98059), confirmed that Src activity is required for the FGF-2-induced phosphorylation of cyclin D2 whereas MAP kinase activity is not. Thus, tyrosine phosphorylation of cyclin D2 may be a key regulatory target for FGF-2 signaling. (C) 2000 Federation of European Biochemical Societies.

DOI 10.1016/S0014-5793(00)01855-X
Citations Scopus - 29
2000 Nurcombe V, Smart CE, Chipperfield H, Cool SM, Boilly B, Hondermarck H, 'The proliferative and migratory activities of breast cancer cells can be differentially regulated by heparan sulfates', Journal of Biological Chemistry, 275 30009-30018 (2000)

To explore how heparan sulfate (HS) controls the responsiveness of the breast cancer cell lines MCF-7 and MDA-MB-231 to fibroblast growth factors (FGFs), we have exposed them to H... [more]

To explore how heparan sulfate (HS) controls the responsiveness of the breast cancer cell lines MCF-7 and MDA-MB-231 to fibroblast growth factors (FGFs), we have exposed them to HS preparations known to have specificity for FGF-1 (HS glycosaminoglycan (HSGAG A)) or FGF-2 (HSGAGB). Proliferation assays confirmed that MCF-7 cells were highly responsive to FGF-2 complexed with GAGB, whereas migration assays indicated that FGF-1/HSGAGA combinations were stimulatory for the highly invasive MDA-MB-231 cells. Quantitative polymerase chain reaction for the levels of FGF receptor (FGFR) isoforms revealed that MCF-7 cells have greater levels of FGFR1 and that MDA-MB-231 cells have greater relative levels of FGFR2. Cross-linking demonstrated that FGF-2/HSGAGB primarily activated FGFR1, which in turn up-regulated the activity of mitogen-activated protein kinase; in contrast, FGF-1/HSGAGA led to the phosphorylation of equal proportions of both FGFR1 and FGFR2, which in turn led to the up-regulation of Src and p125(FAK). MDA-MB-231 cells were particularly responsive to vitronectin substrates in the presence of FGF-1/HSGAGA, and blocking antibodies established that they used the a(v)ß 3 integrin to bind to it. These results suggest that the clustering of particular FGFR configurations on breast cancer cells induced by different HS chains leads to distinct phenotypic behaviors.

Citations Scopus - 68
2000 Le Bourhis X, Toillon RA, Boilly B, Hondermarck H, 'Autocrine and paracrine growth inhibitors of breast cancer cells', Breast Cancer Research and Treatment, 60 251-258 (2000)

Breast epithelial cells produce both mitogens and growth inhibitors which are involved in the control of mammary gland development through autocrine and paracrine pathways. While ... [more]

Breast epithelial cells produce both mitogens and growth inhibitors which are involved in the control of mammary gland development through autocrine and paracrine pathways. While the mechanisms of action of several growth factors have been well established and related strategies proposed for breast cancer therapy, little is known concerning growth inhibitors. In this review, we present an overview of current information about major autocrine and paracrine growth inhibitors of breast epithelial cells, and we discuss their potential functions in the control of breast cancer development.

DOI 10.1023/A:1006461621905
Citations Scopus - 13
2000 Blanckaert VD, Hornez L, Hebbar M, Louchez MM, Hondermarck H, Peyrat JP, 'Distribution and prognostic value of the fibroblast growth factor-2 low-affinity binding sites in human breast cancer', Anticancer Research, 20 3913-3918 (2000)

We performed a competitive binding study with 125 I-labelled FGF (fibroblast growth factor) -2 and unlabelled FGF-2 in an unselected series of two hundred and thirty human primar... [more]

We performed a competitive binding study with 125 I-labelled FGF (fibroblast growth factor) -2 and unlabelled FGF-2 in an unselected series of two hundred and thirty human primary breast cancers. One hundred and ninety-two breast cancer biopsies possessed FGF-2 low-affinity binding sites (FGF-2 LABS). The median dissociation constant was 2.4 nM (range, 1.03-18) and the median concentration of membrane protein was 6187.5 fmol/mg (range, 831 -90000). FGF-2 LABS concentrations were positively correlated to the progesterone receptor level. Cox univariate analyses showed that the FGF-2 LABS (= upper quartile) was associated to a longer overall survival (p = 0.05; RR = 0.042); node involvement, estrogen receptor progesterone receptor and histoprognostic grading were also prognostic. In Cox multivariate analyses, only the progesterone receptor, estrogen receptor, node involvement and FGF-2 LABS were prognostic factors; the FGF-2 LABS were associated with a longer overall survival (p = 0.033; RR = 0.068). The present study showed that FGF-2 LABS have only a limited role as a prognostic factor in breast cancer.

Citations Scopus - 1
2000 Hondermarck H, 'Potential role for NGF in breast cancer', Stem Cells, 18 386-387 (2000)
Citations Scopus - 1
2000 Boilly B, Vercoutter-Edouart AS, Hondermarck H, Nurcombe V, Le Bourhis X, 'FGF signals for cell proliferation and migration through different pathways', Cytokine and Growth Factor Reviews, 11 295-302 (2000)

FGFs are pleiotropic growth factors that control cell proliferation, migration and differentiation. However, FGF transduction studies have so far focused primarily on the mitogeni... [more]

FGFs are pleiotropic growth factors that control cell proliferation, migration and differentiation. However, FGF transduction studies have so far focused primarily on the mitogenic effect of this growth factor family and it has been difficult to assess if the described intracellular signaling pathways are dedicated solely to cell proliferation, or whether they are equally important for the migratory activity often seen in responsive cells. We review here papers in which the migratory effects of this growth factor family were clearly discriminated from proliferative effects. In toto, these studies suggest that cells use different signaling pathways for migration, such as Src and p38 MAP kinase, from those for proliferation, which tend to upregulate the ERKs. Which signaling pathway a cell uses for proliferation or migration appears to depend on many factors, including the structure and the quantity of available FGF trapped in the basal lamina by heparan sulfate co-factors, the disposition of cognate high affinity receptors and the general environment of the cell. Thus the density of the cell population, the state of the cell cycle, the presence of other factors or receptors will modulate the migratory response of cells to FGF. (C) 2000 Elsevier Science Ltd.

DOI 10.1016/S1359-6101(00)00014-9
Citations Scopus - 177
2000 Toillon RA, Adriaenssens E, Wouters D, Lottin S, Boilly B, Hondermarck H, Le Bourhis X, 'Normal breast epithelial cells induce apoptosis of MCF-7 breast cancer cells through a p53-mediated pathway', Molecular Cell Biology Research Communications, 3 338-344 (2000)

Cancer development depends not only on the nature of the tumor cells themselves but also on the regulatory effects of various normal cells. The present study was performed to bett... [more]

Cancer development depends not only on the nature of the tumor cells themselves but also on the regulatory effects of various normal cells. The present study was performed to better understand the mechanism by which normal breast epithelial cells (NBEC) can control the growth of MCF-7 breast cancer cells. When MCF-7 cells were treated with NBEC conditioned medium, cell growth was inhibited in a concentration-dependent manner. This inhibition was due to an induction of apoptosis without any change in cell cycle progression. The induction of apoptosis was correlated with increased levels of p53, p21(waf1) and decreased levels of bcl-2. Transient transfections of MCF-7 cells with two p53 cDNA constructs demonstrafed the induction of apoptosis was mediated by endogenous p53. Taken together, our results indicate that NBEC inhibit the growth of MCF-7 breast cancer cells by inducing apoptosis in them via endogenous p53. (C) 2000 Academic Press.

DOI 10.1006/mcbr.2000.0236
Citations Scopus - 6
2000 Peyrat JP, Recchi MA, Hebbar M, Pawlowski V, Hornez L, Dong-Lebouhris X, et al., 'Regulation of sialyltransferase expression by estradiol and 4-OH- tamoxifen in the human breast cancer cell MCF-7', Molecular Cell Biology Research Communications, 3 48-52 (2000)

We have addressed the effects of estradiol and 4-OH-tamoxifen on the expression of five sialyltransferases in the homono-dependent MCF-7 cell line using a Multiplex RT-PCR approac... [more]

We have addressed the effects of estradiol and 4-OH-tamoxifen on the expression of five sialyltransferases in the homono-dependent MCF-7 cell line using a Multiplex RT-PCR approach. Estradiol induced a statistically significant increase in ST3Gal III and a decrease in ST6Gal I, whereas the two other enzymes, ST3Gal IV and ST3Gal I, are not modified and expression of the fifth enzyme, ST3Gal II, was very low or not detectable. Estradiol effects were dose dependent and completely antagonized by 4OH-tamoxifen. In addition, there is no direct relation between cellular proliferation and sialyltransferase expression. This suggests that ST3Gal III and ST6Gal I could be used as supplementary markers of homono-sensitivity in breast cancer. (C) 2000 Academic Press.

DOI 10.1006/mcbr.2000.0185
Citations Scopus - 12
1998 Lambrecht V, Le Bourhis X, Toillon RA, Boilly B, Hondermarck H, 'Alterations in both heparan sulfate proteoglycans and mitogenic activity of fibroblast growth factor-2 are triggered by inhibitors of proliferation in normal and breast cancer epithelial cells', Experimental Cell Research, 245 239-244 (1998)

Heparan sulfate proteoglycans (HSPG) are involved in the regulation of cellular proliferation, differentiation, and migration. We have studied the effect of three inhibitors of pr... [more]

Heparan sulfate proteoglycans (HSPG) are involved in the regulation of cellular proliferation, differentiation, and migration. We have studied the effect of three inhibitors of proliferation on 35 S incorporation into HSPG of the breast cancer cell lines MCF-7 and MDA-MB-231 and the normal breast epithelial cells (NBEC). Transforming growth factor ß-1 (TGFß-1), which inhibits the proliferation of NBEC, but not of MCF-7 and MDA-MB-231, cells induced an increase in 35 S incorporation of HSPG in NBEC, but had no effect on cancer cells. Sodium butyrate (NAB), which inhibits NBEC as well as cancer cell proliferation, induced an increase in 35 S incorporation into HSPG in all cell types studied. In contrast, retinoic acid had no effect on HSPG of breast epithelial cells. Modification of HSPG induced by TGFß-1 or NaB treatments in normal and breast cancer epithelial cells resulted in an increase in 125 I-fibroblast growth factor-2 (FGF-2) binding on HSPG. More importantly, NaB pretreatment resulted in an inhibition of the MCF-7 cell responsiveness to FGF-2, even though these cells remained sensitive to growth stimulation induced by serum or epidermal growth factor. These results indicate that changes in HSPG production are a key process involved in the mechanism of breast epithelial cell growth regulation.

DOI 10.1006/excr.1998.4199
Citations Scopus - 6
1998 Descamps S, Lebourhis X, Delehedde M, Boilly B, Hondermarck H, 'Nerve growth factor is mitogenic for cancerous but not normal human breast epithelial cells', Journal of Biological Chemistry, 273 16659-16662 (1998)

We show here that nerve growth factor (NGF), the archetypal neurotrophic factor, is able to stimulate the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cell lines), a... [more]

We show here that nerve growth factor (NGF), the archetypal neurotrophic factor, is able to stimulate the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cell lines), although it is unable to stimulate growth of normal breast epithelial cells (NBEC). This stimulation induced cells in the G 0 phase to reenter the cell cycle, as well as shortening cell cycle duration. Immunoblotting experiments revealed that both the two cancer cell lines and the NBEC express high affinity (p140(trk)) and low affinity (p75) NGF receptors. Inhibition of the NGF growth-promoting effect by the drugs K- 252a and PD98059 indicated that activation of Trk-tyrosine kinase activity and the mitogen-activated protein kinase cascade are necessary to obtain the mitogenic effect. Activation of mitogen-activated protein kinase can be detected in breast cancer cells after 10 min of NGF stimulation, whereas no change was detected in NBEC. These results demonstrate that NGF is a mitogenic factor for human breast cancer cells and that it might constitute a new regulator of breast tumor growth.

DOI 10.1074/jbc.273.27.16659
Citations Scopus - 104
1997 Zenjari C, Boilly B, Hondermarck H, Boilly-Marer Y, 'Nerve-blastema interactions induce fibroblast growth factor-1 release during limb regeneration in Pleurodeles waltl', Development Growth and Differentiation, 39 15-22 (1997)

Previous studies have shown that both fibroblast growth factor (FGF)-1 and nerves play an important function during limb regeneration, but no correlation between these two regener... [more]

Previous studies have shown that both fibroblast growth factor (FGF)-1 and nerves play an important function during limb regeneration, but no correlation between these two regeneration factors has yet been demonstrated. In the present study we first establish that exogenous FGF-2, a member of the FGF family that binds to the same high-affinity receptors as FGF-1, is able to stimulate both [ 3 H]-thymidine incorporation and the mitotic index in the mesenchyme and the epidermal cells of denervated blastemas. We then use cocultures of spinal cord and blastema on heparin-coated dishes, an in vitro system mimicking the in vivo interactions during limb regeneration, to show that interactions between nerve fibers from the spinal cord and the blastema enhance the release of bioactive FGF-1. Release of this growth factor seemed to correlate with nerve fiber regeneration, as it decreased in the presence of the dipeptide Leu-Ala, known to inhibit neurite outgrowth, while the inverse dipeptide Ala-Leu was inactive. Therefore, these results support our hypothesis that the interaction between nervous tissue and blastema is permissive for the release of FGF-1, which in turn stimulates blastema cell proliferation.

Citations Scopus - 23
1997 Delehedde M, Deudon E, Boilly B, Hondermarck H, 'Proteoglycans in breast cancer', Pathologie Biologie, 45 305-311 (1997)

Proteoglycans (PG) are complex sulphated macromolecules composed of linear polysaccharide chains of glycosaminoglycans (GAG) covalently attached to a core protein. These GAG chain... [more]

Proteoglycans (PG) are complex sulphated macromolecules composed of linear polysaccharide chains of glycosaminoglycans (GAG) covalently attached to a core protein. These GAG chains contain sulphate groups at various positions, giving them a high density of negative charges, and allowing them to interact with extracellular matrix molecules, including various growth factors. In the developing mammary gland, sulphated proteoglycans participate in morphogenesis and interact with extracellular matrix components in order to constitute a functional matrix. In breast pathogenesis, qualitative or quantitative changes in PG may have important consequences on cell proliferation and/or differentiation. Thus, several studies showed large variations in the nature and distribution of PG/GAG in breast cancer. Accumulation of chondroitin sulfate proteoglycans was described in the stromal compartment of mammary biopsy sections, and content in heparan sulfate proteoglycans, which were more specifically distributed in the epithelial compartment, increased with the level of malignancy and invasiveness of breast cancer tissues. Furthermore, heparan sulfate proteoglycans seem to be involved in control of the growth-promoting activity of numerous growth factors such as fibroblast growth factors also named Heparin-Binding Growth Factors (HBGF). The implication of PG in growth factor activity suggest that PG may have pronostic value in breast cancer. In future, structural studies into the specific HS-sequences involvement in growth factors binding could allow the development of new antiproliferative strategies.

Citations Scopus - 2
1997 Delehedde M, Deudon E, Boilly B, Hondermarck H, 'Production of sulfated proteoglycans by human breast cancer cell lines: Binding to fibroblast growth factor-2', Journal of Cellular Biochemistry, 64 605-617 (1997)

The cellular distribution and nature of proteoglycans synthesized by human breast cancer cells in culture were studied. Proteoglycans were labelled with [ 35 S] sulfate, purified,... [more]

The cellular distribution and nature of proteoglycans synthesized by human breast cancer cells in culture were studied. Proteoglycans were labelled with [ 35 S] sulfate, purified, and characterized after ion-exchange chromatography followed by gel-filtration chromatography and treatment with glycosaminoglycan degrading enzymes. Proteoglycans were isolated from the culture medium and from cell layers of the hormono-dependent well- differentiated MCF-7 cell line, the hormono-independent poorly- differentiated MDA-MB-231 and then HBL-100 cell line which is derived from non malignant breast epithelium. HBL-100 and MDA-MB-231 cells produced larger amounts of proteoglycans which had a lower degree of sulfation than MCF-7 cells. Gel-filtration chromatography on Sepharose CL-6B indicated that HBL- 100 and MDA-MB-231 cells accumulated cell surface heparan sulfate proteoglycans (HSPG), with a high apparent molecular weight (K(av) 0.1). In contrast, the MCF-7 cell monolayers synthesized small sulfated macromolecules (K(av) 0.4) which possessed mostly chondroitin sulfate chains. Moreover, considerable differences in the nature of the sulfated proteoglycans released into the culture medium of these breast epithelial cell lines were observed. MCF-7 cells released into the culture medium HSPG as the main proteoglycan component while MDA-MB-231 and HBL-100 cells released mainly chondroitin sulfate proteoglycans. In these three cell lines, medium-released sulfated macromolecules have a higher hydrodynamic size than cell-associated ones. Proteoglycans purified by ion-exchange chromatography were tested for their ability to bind 125 I FGF-2. We demonstrated that HBL-100 and MDA-MB-231 cells bind more FGF-2 to their heparan sulfate proteoglycans than MCF-7 cells. Taken together, these results suggested that differences in proteoglycan synthesis of human breast epithelial cells could be responsible for differenc es in their proliferative and/or invasive properties.

DOI 10.1002/(SICI)1097-4644(19970315)64:4&amp;lt;605::AID-JCB9&amp;gt;3.0.CO;2-V
Citations Scopus - 12
1996 Hondermarck H, Peyrat J, Scaps P, Jaruga E, Vercoutter AS, Boilly B, 'Two-dimensional electrophoresis analysis of proteins from breast cancer cells MCF-7. Modifications of synthesis induced by FGF-2', Bulletin du Cancer, 83 837-841 (1996)

Using high resolution two-dimensional electrophoresis, we have separated more than 1,000 proteins from the breast cancer cell line MCF-7. Computer assisted analysis of gels allowe... [more]

Using high resolution two-dimensional electrophoresis, we have separated more than 1,000 proteins from the breast cancer cell line MCF-7. Computer assisted analysis of gels allowed us to classify these proteins infunction of their isoelectric point, molecular weight and relative quantity. This data-base will now be used as a powerful tool to identified proteins which synthesis is regulated in various experimental or pathological situations. Thus we studied modifications induced by FGF-2. This growth factor induces the synthesis of four polypeptides which are not detected in cells not stimulated by this factor. In addition, intensity of nine other polypeptides was found increased in presence of FGF-2.

1996 Delehedde M, Deudon E, Boilly B, Hondermarck H, 'Involvement of sulfated proteoglycans in control of MCF-7 breast cancer cell proliferation', Bulletin du Cancer, 83 129-134 (1996)

The MCF-7 breast cancer cells exhibit remarkable growth enhancement in response to basic fibroblast growth factor (FGF-2) stimulation in a dose dependent manner. To investigate th... [more]

The MCF-7 breast cancer cells exhibit remarkable growth enhancement in response to basic fibroblast growth factor (FGF-2) stimulation in a dose dependent manner. To investigate the involvement of proteoglycans on control of FGF-2 induced proliferation, polysaccharide chains were degraded by specific enzymes. Our results showed that MCF-7 cells were unsensitive to FGF-2 after enzymatic degradation of heparin sulfate proteoglycans (HSPG) by heparinase. After metabolic inhibition of sulphation by sodium chlorate, radiolabelled proteoglycans were purified and quantified by ion exchange chromatography. Sodium chlorate treatment reduced by 70% sulfation of proteoglycans. This decrease of sulphation totally inhibited FGF-2-mediated proliferation. The sulphated glycosaminoglycans which were critical in FGF-2-induced proliferation were strictly HSPG, as an addition of heparin in cell culture medium can restore FGF-2 mitogenic activity. In contrast, other glycosaminoglycans (chondroitin sulfate/hyaluronic acid) did not show any effect. These results provide clear evidence for the critical role of HSPG in FGF-2-induced proliferation on MCF-7 breast cancer cells.

Citations Scopus - 2
1996 Taban CH, Hondermarck H, Bradshaw RA, Boilly B, 'Effect of a dipeptide inhibiting ubiquitin-mediated protein degradation on nerve-dependent limb regeneration in the newt', Experientia, 52 865-870 (1996)

The dipeptide Leu-Ala, which inhibits ubiquitin-mediated protein degradation, has been shown to act in vitro as an inhibitor of neurite outgrowth of PC12 cells. Using agarose bead... [more]

The dipeptide Leu-Ala, which inhibits ubiquitin-mediated protein degradation, has been shown to act in vitro as an inhibitor of neurite outgrowth of PC12 cells. Using agarose beads as vehicles, we tested, in vivo, the effect of this dipeptide (and the inactive inverse, Ala-Leu, as a control) on limb regeneration in the newt (Triturus cristatus), a nerve-dependent developmental process. Leu-Ala inhibited the growth of mid-bud blastemas without altering blastema differentiation, while Ala-Leu had no effect. Cytological observations of dipeptide-treated blastemas using Bodian staining or neurofilament antibodies showed that all the blastema tissues were unmodified except with regard to innervation. Leu-Ala-treated blastemas were devoid of nerve fibers in the epidermal cap, while the mesenchyme distal to the dipeptide impregnated bead exhibited fewer nerve fibers than did Ala-Leu-treated blastemas, which were similar to the control nontreated blastemas. Thus, Leu-Ala, in reducing blastema innervation, inhibits its growth in the same manner as surgical denervation.

Citations Scopus - 14
1996 Delehedde M, Deudon E, Boilly B, Hondermarck H, 'Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells', Experimental Cell Research, 229 398-406 (1996)

The human breast cancer cell lines MCF-7 and MDA-MB-231 differ in their responsiveness to fibroblast growth factor-2 (FGF-2). This growth factor stimulates proliferation in well-d... [more]

The human breast cancer cell lines MCF-7 and MDA-MB-231 differ in their responsiveness to fibroblast growth factor-2 (FGF-2). This growth factor stimulates proliferation in well-differentiated MCF-7 cells, whereas the less well-differentiated MDA-MB-231 cells are insensitive to this molecule. To investigate the potential regulation of FGF-2 mitogenic activity by heparan sulfate proteoglycans (HSPG), we have treated human breast cancer cells by glycosaminoglycan degrading enzymes or a metabolic inhibitor of proteoglycan sulfation: sodium chlorate. The interaction between FGF-2 and proteoglycans was assayed by examining the binding of 125 I-FGF-2 to breast cancer cell cultures as well as to cationic membranes loaded with HSPG. Using MCF-7 cells, we showed that heparinase treatment inhibited FGF-2 binding to HSPG and completely abolished FGF-2 induced growth; chlorate treatment of MCF-7 cells decreased FGF-2 binding to HSPG and cell responsiveness in a dose- dependent manner. This demonstrates a requirement of adequately sulfated HSPG for FGF-2 growth-promoting activity on MCF-7 cells. In highly invasive MDA- MB-231 cells which produce twice as much HSPG as MCF-7 cells and which are not normally responsive to exogenously added FGF-2, chlorate treatment decreased FGF-2 binding to HSPG and induced FGF-2 mitogenic effect. This chlorate effect was dose dependent and observed at concentrations of 10-30 mM; higher chlorate concentrations completely abolished the FGF-2 effect. This shows that the HSPG level of sulfation can also negatively regulate the biological activity of FGF-2. Taken together, these results demonstrate a crucial role for HSPG in both positive and negative control of FGF-2 mitogenic activity in breast cancer cell proliferation.

DOI 10.1006/excr.1996.0385
Citations Scopus - 51
1996 Maufroid JP, Bradshaw RA, Boilly B, Hondermarck H, 'Nerve growth factor induced neurite outgrowth from amphibian neuroepithelial precursor cells is prevented by dipeptides inhibiting ubiquitin-mediated proteolysis', International Journal of Developmental Biology, 40 609-611 (1996)

The effect of dipeptides known to inhibit the ubiquitin-mediated proteolysis has been examined on growth factor induced neurite outgrowth from amphibian neuroepithelial precursor ... [more]

The effect of dipeptides known to inhibit the ubiquitin-mediated proteolysis has been examined on growth factor induced neurite outgrowth from amphibian neuroepithelial precursor cells in primary culture. Nerve growth factor (NGF) stimulated neuritogenesis from these cells but fibroblast growth factor 2 (FGF-2) only increased the number of melanophores. The neurite outgrowth induced by NGF was inhibited by the dipeptides blocking the ubiquitin mediated proteolysis (Leu-Ala and Leu-Gly) whereas the inactive control dipeptides (Ala-Leu and Ala-His) had no effect. This suggests that ubiquitin-mediated proteolysis involving the ubiquitin ligase E3 is necessary for growth factor induced neuronal differentiation during the development of the central nervous system.

Citations Scopus - 12
1996 Zenjari C, Boilly-Marer Y, Desbiens X, Oudghir M, Hondermarck H, Boilly B, 'Experimental evidence for FGF-1 control of blastema cell proliferation during limb regeneration of the amphibian Pleurodeles waltl', International Journal of Developmental Biology, 40 965-971 (1996)

During regeneration, blastema cell proliferation depends on several different factors which are, as yet, not fully understood. Previous studies showing the presence of FGF-1 and F... [more]

During regeneration, blastema cell proliferation depends on several different factors which are, as yet, not fully understood. Previous studies showing the presence of FGF-1 and FGF receptors in the limb blastema make FGF-1 a potentially important molecule for limb regeneration but they do not demonstrate that this factor is active during the process. In the present study, we have first of all confirmed the presence of FGF-1 in limb blastemas of the amphibian Pleurodeles waltl using immunochemistry. Second, we provide evidence in vivo that FGF-1 controls blastema cell proliferation by using different reagents which interfere with FGF activity. Sulfated polysaccharides which bind FGFs, such as heparin, l-carrageenan and pentosan polysulfate, are able to decrease both 3 H-thymidine incorporation and the mitotic index in regeneration blastemas. In addition, suramin which inhibits the binding of growth factors to their receptors, induces the same effect. The presence of receptors in blastema cells is also demonstrated by using the FGF-saporin complex which is known to bind to FGF receptors and to kill cells bearing these receptors. This complex decreases the mitotic index in mesenchyme, while saporin alone did not influence cell proliferation. Finally, results obtained using a neutralizing monoclonal antibody against FGF-1 which was able to specifically reduce blastema cell proliferation, suggests that FGF-1 plays an important function in limb regeneration.

Citations Scopus - 17
1995 Boilly B, Hondermarck H, Oudghir M, Deudon E, Boilly-Marer Y, 'Nerve dependent sulphated glycosaminoglycan synthesis in limb regeneration of the newt Pleurodeles waltl', Roux's Archives of Developmental Biology, 204 509-512 (1995)

Denervation of the amputated limb of newts stops the regeneration process by decreasing blastema cell proliferation. We investigated the effect of the denervation on each of the t... [more]

Denervation of the amputated limb of newts stops the regeneration process by decreasing blastema cell proliferation. We investigated the effect of the denervation on each of the two compartments (epidermal cap, mesenchyme) in mid-bud blastemas on the level of sulphated glycosaminoglycans (GAGS). Denervation resulted in an increase of about threefold in the incorporation of [ 35 S] sulphate into mesenchyme GAGs but had no effect on the epidermal cap. The increase of GAG synthesis in the mesenchymal part of the blastema involved both heparan sulphates and chondroitin-dermatan sulphates. Gel filtration showed no change in GAGs size after denervation. These results confirm that the mesenchymal part of the mid-bud blastema is the main target of nerves and, as heparan sulphates are known to store acidic fibroblast growth factor (aFGF), a polypeptide found in the blastema (Boilly et al.. 1991), this suggest that the nerves' effect on glycosaminoglycans turnover could be implicated in the control of bioavailability of this growth factor in the blastema. © 1995 Springer-Verlag.

DOI 10.1007/BF00360859
Citations Scopus - 4
1995 Delehedde M, Boilly B, Hondermarck H, 'Differential responsiveness of human breast cancer cells to basic fibroblast growth factor: A cell kinetics study', Oncology Research, 7 399-405 (1995)

The effects of basic fibroblast growth factor (bFGF) on breast cancer cells are still contradictory and not fully understood. We have studied the effect of bFGF on the cell cycle ... [more]

The effects of basic fibroblast growth factor (bFGF) on breast cancer cells are still contradictory and not fully understood. We have studied the effect of bFGF on the cell cycle kinetics of two breast cancer cell lines (MCF-7 and MDA-MB-231) and an immortalized cell line (HBL-100). The methodology included use of microscopic image analysis with cell numeration, Feulgen staining, Proliferating Cell Nuclear Antigen/Ki-67 immunodetection and bromodeoxyuridine incorporation. We show that bFGF is mitogenic for MCF-7 cells via a mechanism of recruitment of G 0 phase cells to reenter into the cell cycle and by decreasing the G 1 phase length. No effect of bFGF on cell cycle parameters has been found with either highly metastatic MDA-MB-231 cells or immortalized HBL-100 cells. These results reveal differences in bFGF responsiveness of breast epithelial cells. © 1995.

Citations Scopus - 22
1994 Hondermarck H, Mclaughlin CS, Patterson SD, Bradshaw RA, 'Early changes in protein synthesis induced by basic fibroblast growth factor, nerve growth factor, and epidermal growth factor in PC12 pheochromocytoma cells', Proceedings of the National Academy of Sciences of the United States of America, 91 9377-9381 (1994)

Nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) stimulate neuronal differentiation, whereas epidermal growth factor (EGF) promotes only mitogenic responses in ... [more]

Nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) stimulate neuronal differentiation, whereas epidermal growth factor (EGF) promotes only mitogenic responses in PC12 pheochromocytoma cells. The early changes in protein synthesis induced by bFGF, NGF, and EGF in these cells have been determined by two-dimensional PAGE of [ 35 S]methionine-labeled proteins and computerized image analysis. The rate of synthesis of only 29 proteins (out of ¿1500 identified) was found to be modulated during the first several hours of growth factor stimulation. Individually, 12 were affected by EGF, 23 were affected by bFGF, and 20 were affected by NGF. Eight of these were regulated by all three growth factors, while 10 proteins were commonly induced by bFGF and NGF, in accordance with the essentially identical morphological responses induced by these two factors. In addition, the effects of bFGF and NGF were about equally divided between increases and decreases in the rate of synthesis of individual proteins, whereas EGF caused significantly more positive (increased) responses. All proteins modulated by NGF or FGF alone were negative in their response and those induced by only EGF were positive. Of particular interest, the rate of synthesis of two proteins of 55 kDa and pI 5.45 and 5.50 was dramatically and transiently induced during the first 2 hr of bFGF and NGF treatment and was not affected by EGF. This study indicates that all three factors elicit early increases and decreases in the synthesis of a quite limited number of proteins and provides molecular evidence for the specificity of a differentiative vs. a proliferative growth factor-induced signaling pathway in these cells.

Citations Scopus - 31
1994 Bradshaw RA, Fujii R, Hondermarck H, Raffioni S, Wu Y, Yarski MA, 'Polypeptide growth factors: Structure, function and mechanism of action', Pure and Applied Chemistry, 66 9-14 (1994)

Polypeptide growth factors are a diverse group of hormone-like agents that regulate growth and differentiation through cell surface receptors. They are generally represented by ho... [more]

Polypeptide growth factors are a diverse group of hormone-like agents that regulate growth and differentiation through cell surface receptors. They are generally represented by homologous families containing several members with distinct overlapping receptor interactions and hence, responsive tissue specificities. Similarly, their receptors are also clustered in family groups of sequence-related proteins. The neurotrophin group, characterized by its typical prototypical member nerve growth factor (NGF), has four members which interact variably with three receptors of the trk family. The activation of their tyrosine kinases initiates the characteristic responses. In PC12 cells, stimulation by NGF leads to activation of non-receptor tyrosine kinases and several phospholipid dependent pathways. The sum of these signals induce a variety of immediate early response genes that govern the phenotypic response. However, the minimum pathway (and its essential components) is not yet fully defined. © 1994 IUPAC

DOI 10.1351/pac199466010009
1992 Hondermarck H, Sy J, Bradshaw RA, Arfin SM, 'Dipeptide inhibitors of uniquitin-mediated protein turnover prevent growth factor-induced neurite outgrowth in rat pheochromocytoma PC12 cells', Biochemical and Biophysical Research Communications, 189 280-288 (1992)

Dipeptide inhibitors of the ubiquitin-dependent proteolysis pathway governed by N-terminal recognition (N-end rule) in reticulocyte lysates significantly suppress NGF- and bFGF-in... [more]

Dipeptide inhibitors of the ubiquitin-dependent proteolysis pathway governed by N-terminal recognition (N-end rule) in reticulocyte lysates significantly suppress NGF- and bFGF-induced neurite outgrowth in rat pheochromocytoma PC12 cells, but do not cause retraction of already formed neurites. Peptides which do not inhibit proteolysis are also without effect on PC12 cell differentiation. Suppression of neurite outgrowth is readily reversible upon removal of the inhibitors. These data demonstrate a requirement for specific protein turnover in the process of neuron-like differentiation in PC12 cells and provide the first demonstration of a physiological role for the N-end rule. © 1992.

DOI 10.1016/0006-291X(92)91555-5
Citations Scopus - 31
1992 Peyrat JP, Hondermarck H, Hecquet B, Adenis A, Bonneterre J, 'bFGF binding sites in human breast cancer', Bulletin du Cancer, 79 251-260 (1992)

We investigated binding characteristics of bFGF in membranes prepared from 4 human breast cancer cell lines (MCF-7, T-47D, BT-20 and MDA-MB-231) and 38 primary breast cancer biops... [more]

We investigated binding characteristics of bFGF in membranes prepared from 4 human breast cancer cell lines (MCF-7, T-47D, BT-20 and MDA-MB-231) and 38 primary breast cancer biopsies. Results of competitive binding experiments were analysed using the 'Ligand' program to determine binding site concentrations and affinities. bFGF mitogenic activity was also measured by [ 3 H]-thymidine incorporation into DNA of breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (Kd: 0.5 nM). The presence of these high-affinity binding sites was confirmed by saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormono-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, 7-47D, BT-20 and not of MDA-MB-231 cell lines. In breast cancer biopsies, binding sites were detectable in 36/38 cases; high-affinity binding sites (Kd < 1 nM) were present in 19/39 cases and low-affinity binding sites (Kd > 2 nM) were present in 29/36 cases (the 2 classes of binding sites were present in 12 biopsies). No relation between FGF binding sites and node involvement nature or grade of tumor was evidenced. Negative correlations (Spearman test) were found between total bFGF binding site concentrations and estradiol receptor concentrations (P = 0.05) or progesterone receptor concentrations (P = 0.009). The demonstrations of 1), bFGF specific binding sites in breast cancer membranes; and 2) bFGF growth stimulation of some breast cancer cell lines, indicate that this factor could be involved in the growth of most breast cancers, and could act (among other factors) directly on the growth of cancer cells.

Citations Scopus - 6
1992 Hondermarck H, Boilly B, 'Characterization of fibroblast growth factor binding in regenerating limb blastemas of axolotls.', Monographs in developmental biology, 23 110-115 (1992)
Citations Scopus - 2
1992 Blanckaert V, Hondermarck H, Boilly-Marer Y, 'Differential expression of fibroblast growth factor-like molecules and their receptors: a putative role in tissue regeneration and growth in annelids.', Monographs in developmental biology, 23 28-39 (1992)
Citations Scopus - 1
1992 Hondermarck H, Deudon E, Boilly B, 'Embryonic brain-derived heparan sulfate inhibits cellular membrane binding and biological activity of basic fibroblast growth factor', Developmental Brain Research, 68 247-253 (1992)

We have investigated the ability of glycosaminoglycans from embryonic chick brain (15 days old) to interact with basic fibroblast growth factor (bFGF). 35 SO 4 metabolically lab... [more]

We have investigated the ability of glycosaminoglycans from embryonic chick brain (15 days old) to interact with basic fibroblast growth factor (bFGF). 35 SO 4 metabolically labeled glycosaminoglycans were purified and separated on DEAE-cellulose chromatography. Material which eluted between 0.20 and 0.35 M NaCl displaced the binding of [ 125 I]bFGF to brain membrane. This activity was dose-dependent and on the basis to its heparinase sensitivity and chondroitinase insensitivity, has been attributed to heparan sulfate. CL-6B-Sepharose chromatography of this material revealed two glycosaminoglycans of molecular masses of about 15,000 and 65,000. Incubation with [ 125 I]bFGF followed or not by heparinase and chondroitinase treatment of electrotransfert from SDS-PAGE revealed that both of these forms correspond to heparan sulfate chains and bind bFGF. In vitro, embryonic brain-derived heparan sulfate inhibited both bFGF induced [ 3 H]thymidine incorporation in CCL39 cells and neurite outgrowth in PC12 cells. These results suggest that heparan sulfate play an important function in the control of the biological activity of bFGF during brain development. © 1992.

DOI 10.1016/0165-3806(92)90067-7
Citations Scopus - 15
1992 Hondermarck H, Courty J, Dauchel MC, Barritault D, Boilly B, 'High and low affinity membrane binding sites for fibroblast growth factors in the developing chick brain', Neuroscience Letters, 134 247-252 (1992)

Acidic and basic fibroblast growth factors (aFGF and bFGF), two mitogenic, neurotrophic and angiogenic molecules, are present in the embryonic chick brain but their function remai... [more]

Acidic and basic fibroblast growth factors (aFGF and bFGF), two mitogenic, neurotrophic and angiogenic molecules, are present in the embryonic chick brain but their function remains unclear. In order to approach the biological activity of FGFs during brain development, we have looked for their receptors and studied their regulation through chick brain development. Competitive binding studies realized on brain membranes indicated the presence of two classes of FGF binding sites: high affinity binding sites (dissociation constant, K d = 100 pM) and low affinity binding sites (K d = 20 nM). Cross-competition experiments show that these two classes of binding sites both interact with aFGF and bFGF. The number of sites in these two classes of binding sites changes during embryogenesis. On the one hand, the membrane capacity of high affinity sites decreases from E7 (1 ± 0.2 pmol/mg of protein) to E15 (0.5 ± 0.2 pmol/mg of protein); on the other hand, the membrane capacity of low affinity sites increases from E15 (25 ± 4 pmol/mg of protein) to P1 (75 ± 20 pmol/mg of protein). Cross-linking experiments revealed the presence of two putative receptor forms of molecular masses of about 130 and 95 kDa. These results suggest that the biological activity of aFGF and bFGF during brain embryogenesis could be regulated by the expression of high and low affinity binding sites for these growth factors. © 1992.

DOI 10.1016/0304-3940(92)90527-E
Citations Scopus - 8
1992 Blanckaert V, Hondermarck H, Baert JL, Boilly-Marer Y, 'Identification of a heparin-binding growth factor and of its affinity binding sites in the marine annelid Nereis diversicolor', Comparative Biochemistry and Physiology -- Part B: Biochemistry and, 103 991-997 (1992)

1. 1. Fractionation of extracts of the marine annelid Nereis diversicolor by heparin-Sepharose affinity chromatography yielded a peak of mitogenic activity for vertebrate fibrobla... [more]

1. 1. Fractionation of extracts of the marine annelid Nereis diversicolor by heparin-Sepharose affinity chromatography yielded a peak of mitogenic activity for vertebrate fibroblasts. 2. 2. After further purification, the peptide (M r 19,000) was recognized by antibodies to bovine aFGF or bFGF and was designated nHBGF (for nereid heparin-binding growth factor). 3. 3. Scatchard analysis, using bovine [ 125 I]-basic FGF on membrane preparation of Nereis, showed that the tissues of this animal possessed high- and low-affinity binding sites for this growth factor. 4. 4. This binding is challenged by nHBGF. 5. 5. Thus Nereis appears to be the first reported invertebrate possessing a growth factor and its corresponding receptors related to vertebrate FGFs. © 1992.

DOI 10.1016/0305-0491(92)90228-J
Citations Scopus - 3
1992 Peyrat JP, Bonneterre J, Hondermarck H, Hecquet B, Adenis A, Louchez MM, et al., 'Basic fibroblast growth factor (bFGF): Mitogenic activity and binding sites in human breast cancer', Journal of Steroid Biochemistry and Molecular Biology, 43 87-94 (1992)

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitiv... [more]

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitive binding experiments were performed and analyzed using the "Ligand" program. Furthermore bFGF mitogenic activity was measured by [ 3 H]thymidine incorporation into DNA from breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (MCF-7: K d =0.60 nM; T-47D: K d =0.55 nM; BT-20: K d =0.77 nM; MDA-MB-231: K d =0.34 nM). The presence of these high-affinity binding sites was confirmed with saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormone-independent cells (BT-20: K d =2.9 nM; MDA-MB-231: K d =2.7 nM). bFGF stimulated the proliferation of MCF-7, T-47D, BT-20 but not MDA-MB-231 cell lines. With competition experiments, binding sites were detectable in 36/38 breast cancers; high-affinity binding sites (K d < 1 nM) were present in 19/36 cases and low-affinity binding sites (K d > 2 nM) were present in 29/36 cases (the two classes of binding sites were present in 12 breast cancers). No relation between bFGF binding sites and node involvement, histologic type or grading of the tumor was evidenced. There were negative correlations (Spearman test) between total bFGF binding sites and estradiol receptor (P = 0.05) or progesterone receptor (P = 0.009). The demonstration of (1) bFGF specific binding sites in breast cancer membranes, and (2) bFGF growth stimulation of some breast cancer cell lines indicates that this factor may be involved directly in the growth of some breast cancers. © 1992.

DOI 10.1016/0960-0760(92)90191-K
Citations Scopus - 35
1991 Boilly B, Cavanaugh KP, Thomas D, Hondermarck H, Bryant SV, Bradshaw RA, 'Acidic fibroblast growth factor is present in regenerating limb blastemas of axolotls and binds specifically to blastema tissues', Developmental Biology, 145 302-310 (1991)

The growth of regenerating limbs of amphibians depends upon proliferation of the blastema cells that accumulate beneath the epidermal cap. The epidermal cap is known to be mitogen... [more]

The growth of regenerating limbs of amphibians depends upon proliferation of the blastema cells that accumulate beneath the epidermal cap. The epidermal cap is known to be mitogenic for the blastema cells. We have extracted a mitogenic activity from both the mesenchymal and epidermal (epidermal cap) components of cone stage blastemas which is retained on heparin-Sepharose and elutes with 1.15 M NaCl. This fraction stimulates neurite outgrowth of PC12 cells and [ 3 H]thymidine incorporation into CCL 39 cells and is potentiated by heparin. The 2 M fraction was inactive. The heparin-Sepharose-purified growth factor cross-reacts with bovine acidic FGF polyclonal antibodies and shows a M r of 16,000 on Western blots. Blastema membranes contain specific high affinity binding sites (K d = 25 pM; capacity = 30 fmole/mg protein) and low affinity binding sites (K d = 18 nM; capacity = 30 pmole/mg protein) for aFGF as revealed by Scatchard analysis. 125 I-aFGF which is bound specifically by both the epidermal cap and mesenchyme of blastema frozen sections is displaced by an excess of unlabeled factor and inhibited by heparin. Heparinase treatment and 2 M NaCl washing which decreased the binding was fourfold more efficient for epidermal cap than for mesenchyme suggesting the presence of high affinity receptors in the latter tissue. The presence of aFGF (or a closely related molecule) in blastemas is consistent with our earlier results that showed stimula tion of proliferation of cultured blastema cells by acidic or basic FGF or heparin alone. These results suggest the possibility that aFGF is stored in the epidermal cap during limb regeneration and that it stimulates the proliferation of the underlaying mesenchyme. © 1991.

DOI 10.1016/0012-1606(91)90128-P
Citations Scopus - 71
1991 HONDERMARCK H, THOMAS D, COURTY J, BARRITAULT D, BOILLY B, 'Expression of Fibroblast Growth Factor Receptors during Chick Brain Development', Annals of the New York Academy of Sciences, 638 406-408 (1991)
DOI 10.1111/j.1749-6632.1991.tb49054.x
1990 Hondermarck H, Courty J, Ledoux D, Blanckaert V, Barritault D, Boilly B, 'Evidence of high and low affinity binding sites for basic fibroblast growth factor in mouse placenta', Biochemical and Biophysical Research Communications, 169 272-281 (1990)

The placenta has been shown to contain bFGF, but the presence of specific binding sites for this growth factor in this tissue remained to be established. In order to study the rol... [more]

The placenta has been shown to contain bFGF, but the presence of specific binding sites for this growth factor in this tissue remained to be established. In order to study the role of bFGF in the placenta growth, we looked for specific binding sites on mouse placental cell membranes at days 12, 14, 16, and 18 of pregnancy. At day 12, Scatchard analyses indicated that two classes of specific interaction sites for bFGF were detected. One class of high affinity binding sites was characterized by an apparent Kd of 10 pM and a binding capacity of 10 fmoles per mg of membrane protein. A second class of low affinity binding sites was detected with an apparent Kd of 60 nM and a binding capacity of 26 pmoles per mg of membrane protein. At days 14, 16 or 18, Scatchard analyses only showed low affinity binding sites with an apparent Kd of 24 nM and a binding capacity of 230 pmoles per mg of membrane protein. The characterization of these binding sites was performed by cross linking experiments that revealed two forms of specific complexes. This result suggested that the high affinity binding sites correspond to putative receptors with relative molecular masses equal to 65,000 and 85,000. The dramatic decrease of the high affinity receptor number after the 12th day of pregnancy, which is synchronous with the 9-fold increase of the low affinity binding site number, suggests that the biological activity of bFGF could be regulated by a balance between both the numbers of high and low affinity binding sites on placenta cell membranes. Thus, as it was shown for other growth factors, bFGF could only be involved at specific pregnancy stages. © 1990.

DOI 10.1016/0006-291X(90)91464-4
Citations Scopus - 25
1990 Hondermarck H, Courty J, Thomas D, 'Distribution of intravenously administered acidic and basic fibroblast growth factors in the mouse', Experientia, 46 973-974 (1990)

Iodinated acidic or basic fibroblast growth factor (aFGF or bFGF) were separately injected into adult mice to follow their distribution in the main organs of the animals. Iodinate... [more]

Iodinated acidic or basic fibroblast growth factor (aFGF or bFGF) were separately injected into adult mice to follow their distribution in the main organs of the animals. Iodinated FGFs intravenously injected into mice cleared from blood with a T 1/2 of 30 s. They mainly bound to kidney, liver and spleen. The binding of FGFs to these organs was maintained when the latter were washed with a physiological buffer containing 0.15 M NaCl, but it was eliminated when the buffer contained 2 M NaCl. Simultaneous injections of the FGFs together with increasing doses of heparin weakened the binding of FGF to vessels in a dose-dependent manner. © 1990 Birkhäuser Verlag Basel.

DOI 10.1007/BF01939392
Citations Scopus - 28
Show 102 more journal articles

Review (1 outputs)

Year Citation Altmetrics Link
2012 Hondermarck H, 'Neurotrophins and their receptors in breast cancer', Cytokine & Growth Factor Reviews (2012) [C1]
Citations Scopus - 37Web of Science - 34

Conference (20 outputs)

Year Citation Altmetrics Link
2017 Rowe C, Tolosa Gonzalez JT, Faulkner S, Paul JW, Gedye C, McGrath S, et al., 'The precursor for nerve growth factor (proNGF) is detectable in the rinse of fine needle aspiration biopsy of thyroid cancer' (2017)
Co-authors Roger Smith, Christopher W Rowe Uon, Jonathan Paul
2016 Sillar J, Murray H, Al Mazi J, Skerrett-Byrne D, Kahl R, Flanagan H, et al., 'QUANTITATIVE, HIGH-RESOLUTION PROTEOMICS FOR A SYSTEMS BIOLOGICAL ANALYSIS OF ACUTE MYELOID LEUKEMIA', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Matt Dun
2016 Al Mazi JT, Verrills N, Smith N, Pockney P, Hondermarck H, Dun M, 'A COMPARISON BETWEEN DATA-DEPENDENT ANALYSIS AND HIGH-RESOLUTION ACCURATE MASS TARGETED PROTEOMICS APPROACHES FOR THE QUANTIFICATION OF PLASMA BIOMARKERS IN COLORECTAL CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Matt Dun
2016 Faulkner S, Jobling P, Rowe C, Oldmeadow C, Roselli S, Thorne R, et al., 'CLINICOPATHOLOGICAL SIGNIFICANCE OF PRONGF RECEPTORS IN THYROID CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Rick Thorne, Christopher Oldmeadow, Marjorie Walker, John Attia, Phillip Jobling
2016 Li X, Al Mazi J, Smith N, Dun M, Hondermarck H, 'DEVELOPMENT OF A HIGHLY SENSITIVE AND SPECIFIC TARGETED MASS SPECTROMETRY ASSAY FOR PSA IN PROSTATE CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Matt Dun
2016 Pundavela J, Dona A, Walker M, Hondermarck H, Ramadan S, 'A NOVEL SCREENING TEST FOR PROSTATE DISEASE USING NUCLEAR MAGNETIC RESONANCE (NMR)', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Marjorie Walker, Saadallah Ramadan
2016 Oliveira SMR, Roselli S, Hondermarck H, Jobling P, 'OVARIAN TUMORS PRESENT AUTONOMIC AND SENSORY INNERVATION', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2016)
Co-authors Phillip Jobling
2015 Jiang CC, Chi MN, Guo ST, Wilmott JS, Guo XY, Yan XG, et al., 'Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells', CANCER RESEARCH (2015) [E3]
DOI 10.1158/1538-7445.AM2015-4718
Co-authors Lei Jin, Xu Zhang, Chenchen Jiang
2015 Pundavela J, Roselli S, Demont Y, Faulkner S, Attia J, Keene S, et al., 'The neuronal protein sortilin is expressed in aggressive breast cancers and participates in tumor cell growth and invasion', CANCER RESEARCH (2015) [E3]
DOI 10.1158/1538-7445.SABCS14-P6-01-11
Co-authors John Attia, Marjorie Walker
2015 Oliveira S, Roselli S, Hondermarck H, Jobling P, 'Nerve fibers infiltrate ovarian cancer and may be related to tumor aggressiveness', JOURNAL OF NEUROCHEMISTRY (2015) [E3]
Co-authors Phillip Jobling
2015 Faulkner S, Roselli S, Demont Y, Choquet G, Leissner P, Oldmeadow C, et al., 'ProNGF AS A NEW BIOMARKER IN THYROID CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2015) [E3]
Co-authors Christopher Oldmeadow, John Attia, Marjorie Walker
2015 Shargh VH, Hondermarck H, Liang M, 'ENHANCING THE EFFICACY OF TYROSINE KINASE INHIBITORS THROUGH BIO-POLYMERIC ALBUMIN HYBRID NANOPARTICLES IN BREAST CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2015) [E3]
Co-authors Roger Liang
2015 Faulkner S, Lincz L, McElduff P, Scott R, Thorne R, Walker M, et al., 'COMPARING DIGITAL VERSUS VISUAL SCORING METHODS FOR IMMUNOHISTOCHEMICAL STAINING: A CASE STUDY IN THE HUNTER CANCER BIOBANK', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2015) [E3]
Co-authors Rick Thorne, Rodney Scott, Patrick Mcelduff, Marjorie Walker, Lisa Lincz
2014 Dun MD, Chalkley RJ, Keene S, Bradshaw RA, Hondermarck H, 'Proteomics versus Transcriptomics for the Identification of Cancer Biomarkers: the Case of Brain-derived Metastatic Breast Cancer Cells', MOLECULAR & CELLULAR PROTEOMICS (2014) [E3]
Co-authors Matt Dun
2014 Faulkner S, Roselli S, Thorne RF, Scarlett CJ, Walker MM, Hondermarck H, 'PRONGF AND SORTILIN EXPRESSION AND FUNCTION IN PANCREATIC CANCER', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2014) [E3]
Co-authors Marjorie Walker, Rick Thorne, C Scarlett
2014 Shargh VH, Hondermarck H, Liang M, 'MULTIFUNCTIONAL NANOMEDICINES BASED ON ALBUMIN FOR TARGETED BREAST CANCER THERAPY', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2014) [E3]
Co-authors Roger Liang
2014 Oliveira SMR, Roselli S, Hondermarck H, Jobling P, 'PERIPHERAL NERVES ARE ASSOCIATED WITH SOME OVARIAN TUMOURS', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2014) [E3]
Co-authors Phillip Jobling
2013 Ahmed AF, De Bock CE, Sontag E, Hondermarck H, Thorne RF, 'The functional role of Fat1 cadherin in the differentiation and proliferation of SH-SY5Y neuroblastoma cells', - (2013) [E3]
Co-authors Rick Thorne, Estelle Sontag
2012 Roselli SM, Moscato PA, Scott R, Hondermarck H, 'Breast cancer proteomics: Integrating the data with genomics and histology towards clinical applications', 18th Proteomics Symposium. Delegate Handbook (2012) [E3]
Co-authors Rodney Scott, Pablo Moscato
2006 Hondermarck H, 'Proteomics of breast cancer: From differential to functional analysis', Journal de la Societe de Biologie (2006)

From differential analysis to identify biomarkers, to functional analysis for finding new therapeutic targets, proteomics bring new comprehensive information for a better understa... [more]

From differential analysis to identify biomarkers, to functional analysis for finding new therapeutic targets, proteomics bring new comprehensive information for a better understanding of the molecular basis of oncology and new perspectives for the clinic. However the major limitation of proteomic investigations, more generally of post-genomic approaches, remains the molecular and cellular complexity of the mammary gland that is still a major challenge.

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Grants and Funding

Summary

Number of grants 23
Total funding $3,538,607

Click on a grant title below to expand the full details for that specific grant.


20171 grants / $200,000

Targeting Nerves as a New Therapeutic Strategy in Pancreatic Cancer$200,000

Funding body: Maitland Cancer Appeal Committee

Funding body Maitland Cancer Appeal Committee
Project Team Professor Hubert Hondermarck, Doctor Phil Jobling, Professor Marjorie Walker
Scheme Research Project
Role Lead
Funding Start 2017
Funding Finish 2019
GNo G1700836
Type Of Funding Donation - Aust Non Government
Category 3AFD
UON Y

20164 grants / $216,269

A systems biology capability for the Ramaciotti Centre for Genomics$75,592

Funding body: ARC (Australian Research Council)

Funding body ARC (Australian Research Council)
Project Team Associate Professor Stuart Cordwell, Associate Professor Steven Djordjevic, Professor Marc Wilkins, Professor Rick Cavicchioli, Professor Nicolle Packer, Professor Gilles Guillemin, Associate Professor Ann Goodchild, Laureate Professor Rodney Scott, Doctor Rick Thorne, Professor Hubert Hondermarck, Dr Dianne McDougald, Dr Garruy Myers, Professor David James, Professor Stephen Simpson, Professor Richard Payne
Scheme Linkage Infrastructure Equipment & Facilities (LIEF)
Role Investigator
Funding Start 2016
Funding Finish 2016
GNo G1600914
Type Of Funding Scheme excluded from IGS
Category EXCL
UON Y

A systems biology capability for the Ramaciotti Centre for Genomics$72,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Associate Professor Stuart Cordwell, Professor David James, Professor Stephen Simpson, Professor Richard Payne, Professor Rick Cavicchioli, Professor Nicolle Packer, Professor Gilles Guillemin, Associate Professor Ann Goodchild, Laureate Professor Rodney Scott, Doctor Rick Thorne, Professor Hubert Hondermarck, Associate Professor Steven Djordjevic, Dr Dianne McDougald, Dr Garruy Myers
Scheme Equipment Grant
Role Investigator
Funding Start 2016
Funding Finish 2016
GNo G1500600
Type Of Funding Internal
Category INTE
UON Y

A novel biomarker and innovative therapeutic strategy for oesophageal cancer$48,677

Funding body: Hunter New England Local Health District

Funding body Hunter New England Local Health District
Project Team Professor Hubert Hondermarck, Professor Marjorie Walker, Doctor Vanessa Wills, Doctor Phil Jobling, Professor John Attia, Professor Robert Rush
Scheme Project Grant
Role Lead
Funding Start 2016
Funding Finish 2016
GNo G1601109
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Neurotrophins and their receptors as clinical biomarkers and therapeutic targets in prostate cancer.$20,000

Funding body: Hunter Cancer Research Alliance

Funding body Hunter Cancer Research Alliance
Project Team

Phil Jobling, Marjorie Walker, Martin Jarad, Christopher Oldmeadow, Robert Rush, Jay Pundavela, Sam Faulkner, Alison Rutledge, Sonia Rodriguez Oliveira

Scheme Pilot Project
Role Lead
Funding Start 2016
Funding Finish 2017
GNo
Type Of Funding Other Public Sector - Local
Category 2OPL
UON N

20155 grants / $1,211,250

High resolution fourier transform mass spectrometry platform for the discovery of novel cancer biomarkers and drug targets using label-free and isobaric-tagged approaches for quantitative proteomics.$500,000

Funding body: Cancer Institute NSW

Funding body Cancer Institute NSW
Project Team Professor Xu Dong Zhang, Doctor Matt Dun, Professor Jennifer Martin, Professor Hubert Hondermarck, Laureate Professor John Aitken, Doctor Nikki Verrills, Doctor Pradeep Tanwar, Laureate Professor Rodney Scott, Professor Maria Kavallaris, Dr Darren Saunders
Scheme Research Equipment Grant
Role Investigator
Funding Start 2015
Funding Finish 2016
GNo G1500599
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Advanced Technical Support for Oncology Single Cell Analysis Technologies$300,000

Funding body: Cancer Institute NSW

Funding body Cancer Institute NSW
Project Team Laureate Professor Rodney Scott, Professor Xu Dong Zhang, Professor Hubert Hondermarck, Conjoint Professor Stephen Ackland, Doctor Craig Gedye, Doctor Pradeep Tanwar, Doctor Chen Chen Jiang, Doctor Matt Dun, Professor Paul de Souza, Associate Professor Kevin Spring, Dr Tao Liu
Scheme Research Infrastructure Grants
Role Investigator
Funding Start 2015
Funding Finish 2018
GNo G1500824
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Inhibiting Trk tyrosine kinase receptors in cancer$200,000

Inhibiting Trk tyrosine kinase receptors in cancer

Funding body: Ignyta Inc. (San Diego, California)

Funding body Ignyta Inc. (San Diego, California)
Project Team

Hubert Hondermarck

Scheme Private
Role Lead
Funding Start 2015
Funding Finish 2015
GNo
Type Of Funding International - Non Competitive
Category 3IFB
UON N

High resolution fourier transform mass spectrometry platform for the discovery of novel cancer biomarkers and drug targets using label-free and isobaric-tagged approaches for quantitative proteomics.$196,250

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Professor Xu Dong Zhang, Doctor Matt Dun, Professor Jennifer Martin, Professor Hubert Hondermarck, Laureate Professor John Aitken, Doctor Nikki Verrills, Doctor Pradeep Tanwar, Laureate Professor Rodney Scott, Professor Maria Kavallaris, Dr Darren Saunders
Scheme Equipment Grant
Role Investigator
Funding Start 2015
Funding Finish 2015
GNo G1500935
Type Of Funding Internal
Category INTE
UON Y

Nerves and Neurotrophins as New Therapeutic Targets in Cervical Cancer$15,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Professor Hubert Hondermarck, Doctor Phil Jobling, Professor Marjorie Walker, Ms Janine Lombard, Doctor Jay Pundavela
Scheme Project Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1501579
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20144 grants / $499,487

High Throughput Image Capture Platform for Translational Cancer Research$282,614

Funding body: Cancer Institute NSW

Funding body Cancer Institute NSW
Project Team Conjoint Professor Stephen Ackland, Laureate Professor Rodney Scott, Professor John Forbes, Professor Xu Dong Zhang, Professor Marjorie Walker, Professor Hubert Hondermarck, Doctor Craig Gedye, Doctor Rick Thorne, Mr Loui Rassam, Doctor Stephen Braye
Scheme Research Equipment Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1400626
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

Visualisation of microparticles for development of biomarkers and targeted drug delivery mechanisms$125,199

Funding body: Cancer Institute NSW

Funding body Cancer Institute NSW
Project Team Associate Professor Christopher Scarlett, Doctor Kathryn Skelding, Doctor Jude Weidenhofer, Doctor Matt Dun, Doctor Kelly Kiejda, Professor Adam McCluskey, Ms Elham Sadeqzadeh, Professor Hubert Hondermarck, Doctor Rick Thorne, Laureate Professor Rodney Scott
Scheme Research Equipment Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1400627
Type Of Funding Other Public Sector - State
Category 2OPS
UON Y

JuLI Stage $71,674

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Pradeep Tanwar, Professor Eileen McLaughlin, Professor Robin Callister, Professor Xu Dong Zhang, Professor Murray Cairns, Professor Brett Nixon, Professor Hubert Hondermarck, Associate Professor Phillip Dickson, Doctor Nikki Verrills, Doctor Matt Dun, Doctor Jessie Sutherland, Doctor Janani Kumar, Doctor Jay Horvat, Doctor Susan Hua, Associate Professor Liz Milward, Associate Professor Estelle Sontag, Professor Dirk Van Helden, Doctor Janet Bristow, Doctor Jean-Marie Sontag
Scheme Equipment Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1500860
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

Prostate Cancer: A new protein for improving diagnosis, prognosis and treatment$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Severine Roselli, Professor Hubert Hondermarck
Scheme Project Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1401520
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20134 grants / $361,096

Triple Quadrupole Mass Spectrometer with nano-infusion for targeted protein quantification$300,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Associate Professor Mark Baker, Laureate Professor John Aitken, Conjoint Professor Bogdan Dlugogorski, Professor Hubert Hondermarck
Scheme Equipment Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1200137
Type Of Funding Internal
Category INTE
UON Y

12th World Congress of the Human Proteome Organization (HUPO), Yokohama Japan, 14 - 18 September 2013$1,500

Funding body: University of Newcastle - Faculty of Health and Medicine

Funding body University of Newcastle - Faculty of Health and Medicine
Project Team Professor Hubert Hondermarck
Scheme Travel Grant
Role Lead
Funding Start 2013
Funding Finish 2013
GNo G1300864
Type Of Funding Internal
Category INTE
UON Y

20124 grants / $494,694

High-Resolution Isoelectric Phosphoprotein Signalling System for Signalling Research, Biomarker Validation and Drug Development – Equipment Grant$143,394

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Rick Thorne, Professor Xu Dong Zhang, Professor Hubert Hondermarck, Conjoint Professor Stephen Ackland, Doctor Lisa Lincz, Doctor Jennette Sakoff, Emeritus Professor Leonie Ashman
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1200555
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

Microscopic illumination system for advanced fluorescent protein technology$34,000

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Rick Thorne, Professor Xu Dong Zhang, Professor Murray Cairns, Doctor Nikki Verrills, Doctor Charles De Bock, Doctor Jude Weidenhofer, Doctor Severine Roselli, Doctor Kathryn Skelding, Emeritus Professor Leonie Ashman, Professor Hubert Hondermarck
Scheme Equipment Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1100983
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

Does Ubiquitination control the altered expression of tetraspanin proteins in Breast Cancer?$25,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Jude Weidenhofer, Emeritus Professor Leonie Ashman, Professor Hubert Hondermarck
Scheme Project Grant
Role Investigator
Funding Start 2012
Funding Finish 2012
GNo G1200169
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

20111 grants / $555,811

Priority Research Centre for Cancer$555,811

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Conjoint Professor Stephen Ackland, Professor Xu Dong Zhang, Professor John Forbes, Emeritus Professor Leonie Ashman, Doctor Nikola Bowden, Professor Gordon Burns, Conjoint Professor Jim Denham, Professor Hubert Hondermarck, Doctor Lisa Lincz, Doctor Jennette Sakoff, Associate Professor Peter Stanwell, Doctor Rick Thorne, Doctor Nikki Verrills
Scheme Priority Research Centre
Role Investigator
Funding Start 2011
Funding Finish 2016
GNo G1101013
Type Of Funding Internal
Category INTE
UON Y
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Research Supervision

Number of supervisions

Completed4
Current15

Total current UON EFTSL

PhD4.45

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2017 PhD Neuro-Cancer Crosstalk in Pancreatic Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Comparison of Histone Post-translational Modifications in Sperm Cells of Infertile and Fertile Men by Mass Spectrometry. PhD (Biological Sciences), Faculty of Science, The University of Newcastle Co-Supervisor
2017 PhD Neurotrophic growth factors and their receptors as biomarkers and therapeutic targets in human cancers PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Nerve Infiltration and its Impact in Breast and Prostate Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD A Novel Biomarker and Innovative Therapeutic Strategy for Oesophageal Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Nerve Dependence in Human Cancers PhD (Medicine), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2015 PhD The Role of mTOR Hyperactivation in the Pathogenesis of PCOS PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Early serous ovarian carcinogenesis : Understanding the genetic and lifestyle factors PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Genesis of ovarian cancer: understanding the mechanisms of oviductal epithelial cell homoeostasis PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Targeting Thyroid Cancer Cells for Diagnosis and Treatment PhD (Medicine), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2014 PhD ProNGF, NGF and their Receptors in Tumour Innervation and Progression: a Study in Breast and Thyroid Cancers PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2014 PhD The Nerve-Cancer Connection in Ovarian Cancer PhD (Human Physiology), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2014 PhD Role of mTOR signalling in Ovarian Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2014 PhD To Study the Female Lower Reproductive Tract Cell Dynamics, Homeostasis and Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2013 PhD Role of WNT Signalling in Endometrial Homeostasis and Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2017 PhD Multifunctional Nanomedicines Based on Albumin for Targeted Breast Cancer Therapy PhD (Pharmacy), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2017 PhD Wnt Signalling in Germ Cells and Reproductive Tract Development PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Role of FAT1 Cadherin in Neuronal Differentiation PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD ProNGF/NGF and Nerve Infiltration in Prostate and Breast Cancer PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
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News

Hubert Hondermarck

Study strikes a nerve with the spread of cancer

March 27, 2017

A group led by University of Newcastle biochemistry researcher Hubert Hondermarck has found parallels between tissue regeneration, nerve growth and tumour development, confirming for the first time that the nervous system is strongly implicated in the onset and spread of cancer.

John Forbes

International spotlight on cancer research

October 23, 2013

Four of North America's leading cancer researchers will give keynote presentations at the international Translational Cancer Research Conference in Newcastle from tomorrow until Friday.

Professor Hubert Hondermarck

Position

Professor
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Medical Biochemistry

Contact Details

Email hubert.hondermarck@newcastle.edu.au
Phone (02) 4921 8830
Fax (02) 4921 7903

Office

Room LS3-35
Building Life Sciences
Location Callaghan
University Drive
Callaghan, NSW 2308
Australia
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