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Rendering DNA Repair Defective by Targeting Wild-type BRCA1 Nuclear Shuttling in Sporadic Breast Cancer as a Therapeutic Agent

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Annual rept. 1 Sep 2008-31 Aug 2009

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Agents targeting DNA double strand break repair DSBR deficiency, such as PARP1 inhibitors, are highly selective in killing BRCA1- mutated breast tumors, and the toxicity is minimal in mouse models. However, more than 90 of breast cancers are sporadic, which carry wild-type wt BRCA1 and are proficient in DSBR. BRCA1 is a nuclear shuttling protein, which regulates homologues recombination HR-mediated DSBR when nuclear and enhances apoptosis when cytoplasmic. BARD1 retains BRCA1 in the nucleus, whereas ionizing radiation IR induces cell cycle-independent export of BRCA1 to the cytosol. Both BARD1 and IR induce BRCA1 shuttling via the CRM1exportin pathway. It is hypothesized that targeting BRCA1 from the nucleus to the cytoplasm will render cells defective in DSBR and enhance apoptosis. The combination of induced repair deficiency and augmented apoptosis will render sporadic breast cancers highly susceptible to selective killing by agents targeting DNA DSB lesions. This study will determine if targeting BRCA1 from the nucleus to the cytosol using IR and tr-BRCA1, which releases BRCA1 from BARD1 in nuclear, will compromise DSBR and result in a pro-apoptotic environment which renders tumor cells susceptible to PARP1 inhibitor-induced cytotoxicity. Both BRCA1-proficient human breast cancer cell lines and mouse breast tumor models will be used. DSBR will be measured in vivo using a bioluminescenceGFP reporter system. Cytotoxic response to PARP-1 inhibitor will be determined by colony formation in vitro, tumor growth delay in vivo, and cleaved caspase-3 and annexin-V staining for apoptosis in vivo and in vitro.

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  • Medicine and Medical Research

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