p53, BRCA1 and breast Cancer chemoresistance.

The tumor suppressor genes p53 and BRCA1 are involved in hereditary as well as sporadic breast cancer development and therapeutic responses. While p53 mutations contribute to resistance to chemo- and radiotherapy, BRCA1 dysfunction leads to enhanced sensitivity to DNA damaging therapeutic agents. The biochemical pathways used by p53 and BRCA1 for signaling tumor suppression involve some cross-talk including repression of BRCA1 transcription by p53 and altered selectivity of p53-dependent gene activation by BRCA1. In this chapter we review clinical and preclinical data implicating p53 and BRCA1 in breast cancer chemosensitivity. We discuss the known signaling pathways downstream of p53 or BRCA1 that contribute to their modulation of therapeutic responses, and we discuss the implications of p53 or BRCA1 mutation in therapeutic design.