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Targeting defective DNA repair for the prevention of BRCA1-associated cancers

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This proposal describes a career development plan for Elizabeth Alli, PhD to transition into an independent academic position. She has research experience with breast and ovarian cancer, BRCA1, DNA damage and response pathways, and targeted therapeutics, as well as experience with multiple facets of an academic career (e.g. teaching, mentoring, grant writing, data dissemination, etc.). Her long-term career goal is to hold a tenured position with a strong research program that significantly advances the prevention and therapeutic options for BRCA1-mutated or other DNA repair-compromised cancers. Therefore, she has set short-term career goals and objectives that will be met systematically through 1) research activities aimed to develop her skills in the chemoprevention of cancer and 2) ancillary activities that support an independent academic career. Carriers of mutations in the BRCA1 tumor suppressor gene have an increased risk for developing breast and ovarian cancer. Cancers that arise from BRCA1 mutations are often associated with an aggressive clinical course due in part to their tendency to be triple negative, i.e. estrogen receptor-negative, progesterone receptor-negative, and HER2/neu-negative. Current FDA-approved chemoprevention agents for breast cancer target the estrogen receptor, and are thereby ineffective in the mutant BRCA1 setting. Mechanisms that contribute to the tumorigenesis of these cancers, such as compromised DNA base-excision repair (BER) of oxidative DNA damage (ODD), may be used to develop more effective strategies for prevention. The hypothesis states that repair of oxidative DNA damage may be enhanced to prevent tumorigenesis of BRCA1- associated breast cancer. The rationale for this hypothesis is based on the previous discovery of the applicant that BRCA1-mutation or deficiency results in defective BER of ODD, which may act as a functional target for the chemoprevention of BRCA1-associated cancers. She has also carried out a high-throughput chemical screen to identify small molecules that enhance the ability to repair ODD by BER in the presence of mutant BRCA1. These molecules are referred to as DNA repair activators. Therefore, the following specific aims will be addressed: (1) determine the molecular effects of DNA repair activators on base-excision repair of oxidative DNA damage and (2) test the effect of DNA repair activators on BRCA1-associated tumorigenesis. First, for BER activity to prevent tumorigenesis, BER enzymes and proteins must be available in the appropriate location to carry out their function. Therefore, I will take a biochemical approach to determine the effect of DNA repair activators on the expression, localization, and activity of each major BER enzyme (or protein). Second, I will establish in vitro and in vivo BRCA1-models for chemoprevention and use them to assess the effect of DNA repair activators on BRCA1-associated mutagenesis, genetic instability, and tumorigenesis. Overall, this proposal will lead to the use of DNA repair activators as molecular probes in basic science research to study BER of ODD and/or as potential chemoprevention agents to reduce the risk and frequency of BRCA1-associated malignancies.
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