Hereditary mutations in the BRCA1 gene predispose carriers to ovarian cancer. The BRCA1 protein is involved in repairing DNA damage induced by chemotherapies such as platinum and PARP inhibitors (PARPi) using a DNA repair process known as homologous recombination. BRCA1 mutations often render the protein product dysfunctional, consequently tumors cannot repair DNA damage caused by chemotherapy, and so these types of tumors are highly sensitive to DNA damaging agents. However, patients with BRCA1 mutant cancers often develop drug resistance and DNA damage can be repaired once more. In this study, we aim to improve the current understanding of BRCA1 mutant cancer biology.
We compiled a panel of cancer cell lines and compared accumulation of DNA damage response proteins at sites of DNA damage in BRCA1 mutant cancer cells and cancer cells with functional BRCA1. We discovered that BRCA1 mutant cell lines exhibit reduced accumulation of 53BP1 at sites of DNA damage. 53BP1 is a DNA damage response protein that counteracts BRCA1 activity and prevents repair by homologous recombination. Therefore, we suspect that the reduced 53BP1 accumulation allows BRCA1 mutant cancer cells to repair DNA damage and continue to grow. To determine the cause of reduced 53BP1 accumulation, we examined the proteins responsible for recruiting 53BP1 to DNA damage and found one of those proteins, RNF168, to be significantly reduced in the BRCA1 mutant cancer cell lines. Furthermore, we examined patient ovarian tumor samples and found that patients with BRCA1 mutations also exhibited a reduction in RNF168. We hypothesize that BRCA1 mutant cancers reduce RNF168 to prevent 53BP1 accumulation at sites of DNA damage, which allows for repair of DNA damage and cell growth.
Ultimately, we hope to translate this improved understanding of DNA repair in BRCA1 mutant cancers into new strategies for improving patient outcome. Our goal is to generate information that leads to better predictions of therapy responsiveness and novel therapeutic approaches for BRCA1 mutant ovarian cancers.
This grant was made possible by a generous donation by Phil and Judy Messing, in memory of Carol Messing.