Abstract 2966: Targeting defective DNA repair as a novel chemoprevention strategy for BRCA1-mutated breast cancer

Abstract

Abstract Carriers of germline mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1) have an increased risk for developing breast cancer. Unfortunately, BRCA1-mutated cancers are not amenable to current chemoprevention options, often associate with an aggressive clinical course, and thus, are in need of an effective prevention strategy. We previously found that BRCA1 plays a role in DNA base-excision repair (BER) of oxidative DNA damage, and that BRCA1-mutated breast cancers exhibit a compromised ability for BER of oxidative DNA damage. Given that excessive oxidative DNA damage leads to tumorigenesis, we hypothesized that small molecules may be used to enhance the repair of oxidative DNA damage, and in turn, prevent tumorigenesis of BRCA1-mutated breast cancer cells. First, a high-throughput chemical screen identified small molecules that enhance BER of oxidative DNA damage in the presence of mutant BRCA1. These molecules have been termed DNA repair-activating agents. At least two DNA repair-activating agents significantly enhanced BER in mutant BRCA1 but not wild-type BRCA1 cell lines. These molecules also decreased basal levels of oxidative DNA damage as determined by flow cytometry using a FITC-conjugated 8oxoG-binding protein and decreased H2O2-induced oxidative DNA damage as determined by the alkaline comet assay modified for detection of oxidized lesions. Both DNA repair-activating agents directly activated BER, rather than indirectly as a result of induction of DNA damage, as evidenced by the alkaline comet assay for DNA strand breaks. Both agents also showed no cytotoxicity at concentrations that enhanced BER of oxidative DNA damage, which is ideal for chemoprevention. Finally, at least one of the DNA repair-activating agents decreased BRCA1-associated tumorigenesis in vitro and in vivo. The DNA repair-activating agent decreased anchorage-independent growth of BRCA1-mutant/deficient cells without a significant effect on cell viability, as well as delayed tumor formation and decreased tumor burden in a dose-response manner in a xenograft mouse model. Taken together, these data suggest that enhancing DNA base-excision repair of oxidative DNA damage may be a novel strategy for the targeted chemoprevention of BRCA1-associated breast cancers. Citation Format: Elizabeth Alli, David Solow-Cordero, Stephanie C. Casey, James M. Ford. Targeting defective DNA repair as a novel chemoprevention strategy for BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2014-2966