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 regimens for several cancers.