YB-1 is a member of a family of DNA-binding proteins containing a cold shock domain. In recent years, several laboratories have demonstrated that YB-1 is directly involved in the cellular response to genotoxic stress. Upon cisplatin treatments, YB-1 translocates from the cytoplasm to the nucleus. 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. Recently, we have observed that YB-1 activates the DNA repair enzyme hNTH1 upon cisplatin treatments. All these observations suggest that YB-1 is directly involved in DNA repair and is important in conferring drug resistance of tumor cells. Additional data indicates that overexpression of YB-1 in tumor cells generates several chemoresistance signatures apparent by microarray expression analyses. The principal objective of this project is to identify proteins associated with YB-1 in cisplatin resistance and to isolate small interference RNAs against these YB-1 protein partners to potentiate cisplatin treatments. The understanding of the molecules through which YB-1 confers drug resistance in tumor cells, will allow us to design better strategies (or new therapeutic drugs) to control cancer progression.