The goal of our work is to identify BRCA1 patients most likely to gain therapeutic benefit from platinum or PARP inhibitor therapy, and understand how tumors that are initially drug sensitive develop resistance. There are approximately 55,000 deaths from breast and ovarian cancer annually in the United States, with BRCA mutations found in 5% to 7% of breast and 6% to 15% of ovarian cancer cases. The emergence of poly(ADP- ribose) polymerase (PARP) inhibitor therapies that exploit DNA repair defects associated with BRCA lesions promises to extend the lives of BRCA mutation-carrying patients. Our preliminary studies have led us to hypothesize that a subset of common cancer-predisposing germline BRCA1 mutations produce semi-functional truncated isoforms that contribute to drug resistance. The expression of alternatively spliced BRCA1 isoforms has been well documented in cell lines and tumors, but because isoforms lack regions of the full-length protein thought to be essential, it has been assumed that these proteins have a limited role in mammalian cell biology. In studies of BRCA1 mutation bearing cell lines that have acquired resistance to PARP inhibitors, we have discovered important roles for specific BRCA1 protein isoforms in DNA repair and drug resistance. Our preliminary data suggest that after selection for PARP inhibitor resistance, cells with BRCA1 exon 11 frameshift mutations preferentially express exon 11-deleted BRCA1 isoforms (BRCA1- 11). BRCA1- 11 proteins retain the N-terminal RING and C-terminal BRCT domains that are important for homologous recombination (HR) DNA repair. Furthermore, elevated expression of BRCA1- 11 protein is crucial for PARP inhibitor and platinum resistance. In this application, we will further identify and characterize BRCA1 isoforms that are capable of contributing to DNA repair and drug resistance. In Aim 1, isoforms that are expressed in BRCA1 mutant patient tumors will be cloned and over-expressed. In Aim 2, we will assess the impact of peptide regions deleted from BRCA1 isoforms on the DNA damage response and their ability to provide therapy resistance. Our work will provide new insights into the current understanding of drug resistance in BRCA1 mutant disease and could be useful for predicting which patients will have lasting responses to PARP inhibitor or platinum therapy. PUBLIC HEALTH RELEVANCE: There are approximately 55,000 deaths from breast and ovarian cancer annually in the United States, with BRCA mutations found in 5% to 7% of breast and 6% to 15% of ovarian cancers cases. The emergence of PARP inhibitor therapy and the ability to exploit DNA repair defects provides considerable promise for extending the lives of BRCA mutation carrying patients. The goal of this project is to improve the application of DNA repair-targeting therapies for the treatment of BRCA1 mutant breast and ovarian cancer.