Abstract A043: Targeting defective DNA repair for the prevention of BRCA1-mutated breast cancer

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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 (ODD), and that BRCA1-mutated breast cancers exhibit a compromised ability for BER of ODD. Given that excessive ODD leads to tumorigenesis, we hypothesized that repair of ODD may be enhanced to prevent tumorigenesis of BRCA1-mutated breast cancer. To test this hypothesis, we first identified drugs that enhance BER of ODD in the presence of mutant BRCA1. To do so, we conducted a high-throughput chemical screen using small molecules with known pharmacological activity. Two of these compounds, which have been approved for other clinical indications, enhanced BER in mutant BRCA1 but not wild-type BRCA1 cell lines. These molecules also decreased basal levels of ODD as determined by flow cytometry using a FITC-conjugated 8oxoG-binding protein and decreased H2O2-induced ODD as determined by the alkaline comet assay modified for detection of oxidized lesions. Second, we analyzed certain effects of these drugs that would negatively affect their ability to function as chemoprevention agents. Both drugs showed no cytotoxicity at concentrations that enhanced BER of ODD as seen by the MTT assay and Hoechst-staining for live cells. Both drugs 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. Finally, at least one of these drugs decreased in vitro tumorigenesis of BRCA1-mutant and isogenic BRCA1-deficient cells using the soft agar colony formation assay and simultaneously had no significant effect on cell viability as determined by the trypan blue exclusion assay. Taken together, these data suggest a novel strategy for the targeted chemoprevention of BRCA1-associated breast cancers. Citation Format: Elizabeth Alli, Dave Solow-Cordero. Targeting defective DNA repair for the prevention of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A043.