Title:
Professor

Institute:
Laval University

Department:
Department of molecular biology, medical biochemistry, and pathology

Province:
Quebec

Training:
Postdoctoral fellow, Department of Genetics, Harvard Medical School, Boston, MA, USA
PhD, Montreal Cancer Institute, Montreal University, Montreal, Quebec, Canada
BSc, Department of biology, McGill University, Montreal, Quebec, Canada

Research interests:
Cancer progression, chemoresistance, breast and ovarian cancers

Recognitions and awards:
FRSQ Senior scholar

Career highlights:
Identification of the potential mechanisms implicating YB-1 in cisplatin resistance in breast cancer; Identification of the whole YB-1 proteome in breast cancer; Identification of protein interactants required for YB-1 to confer cisplatin resistance in breast cancer cell lines.
 

Research Projects

Project title:
Identification of molecules that will inhibit chemoresistance conferred by YB-1 in breast tumors

Funding period:
2011-2013

Program:
Operating Grant (Basic Research)

Summary:
The YB-1 protein is a member of a family of RNA and DNA-binding factors important for the synthesis of several cellular proteins. In recent years, several laboratories have demonstrated that YB-1 is directly involved in the cellular response to cytotoxic stress. Upon cisplatin treatments (often used as first line regimen during chemotherapy), YB-1 translocates from the cytoplasm to the nucleus where it confers resistance. Interestingly, YB-1 is increased in tumor cultured cell lines resistant to cisplatin. In fact, several studies have indicated that the level of nuclear expression of YB-1 is predictive of drug resistance and patient outcome in breast and ovarian cancers. Drug resistance is a major cause of death in women diagnosed with breast cancer. Recently, we have observed that YB-1 activates the DNA repair enzyme hNTH1 upon cisplatin treatments also conferring resistance. In addition, we identified the small ribosomal protein 4X (RPS4X) that binds to YB-1 in tumor cells and that is also important for cisplatin resistance. The principal objective of this application is to identify cell permeable peptides that will go into tumor cells and disrupt the interaction of the YB-1/hNTH1 or the YB-1/RPS4X complexes and to test their efficacy in sensitizing YB-1 overexpressing (thus chemoresistant) breast tumor cell lines to cisplatin, a known first line chemotherapeutic regimen for several cancers.

CRS publications:

Gaudreault, I., Guay, D., and Lebel, M. (2004) YB-1 promotes strand separation of duplex DNA containing either mispaired bases or cisplatin modifications, exhibits endonucleolytic activities, and binds several DNA repair proteins. Nucleic Acids Research, 32: 316-327.

Guay, D., Gaudreault, I., Massip, L. and Lebel, M. (2006) Formation of a nuclear complex containing the p53 tumor suppressor, YB-1, and the Werner Syndrome gene product in cells treated with UV light. The International Journal of Biochemistry & Cell Biology, 38:1300-1313.

Guay, D., Garand, C., Reddy, S., Schmutte, C., and Lebel, M. (2008) .The human NTH1 enzyme is a relevant target to potentiate cisplatin cytotoxicity in YB-1 overexpressing tumor cells. Cancer Science, 99: 762-769.

Guay, D., Evoy, A.-A., Paquet, E., Garand, C., Bachvarova, M., Bachvarov, D., and Lebel, M. (2008) The strand separation and nuclease activities associated with YB-1 are dispensable for cisplatin resistance but overexpression of YB-1 in MCF7 and MDA-MB-231 breast tumor cells generates several chemoresistance signatures, The International Journal of Biochemistry & Cell Biology, 40: 2492–2507.

de Souza-Pinto, N.C., Mason, P.A., Hashiguchi, K., Weissman, L., Tian, J., Guay, D., Lebel, M., Stevnsner, T.V., Rasmussen, L.J., and Bohr, V.A. (2009) Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amsterdam), 8: 704-719.

Garand, C., Guay, D., Sereduk, C., Chow, D., Tsofack, S. P., Langlois, M., Perreault, È., Yin, H.H., and Lebel, M. (2011) A new integrative approach to identify YB-1 interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cell lines. Cancer Science, 102: 1410-1417.

Past CRS projects:

2008 Molecular mechanisms of resistance to anti-cancer drugs by the overexpression of YB-1 protein in breast tumors.

2006 Molecular mechanisms of resistance to anti-cancer drugs by the overexpression of YB-1 protein in breast tumors.

2004 Molecular mechanisms of resistance to anti-cancer drugs by the overexpression of YB-1 protein in breast tumors.