The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathway of DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment of nucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has been shown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities of BRCA1 can be reconciled in HR repair. From a cancer pathophysiological perspective, most BRCA1- associated breast tumors are basal-like but they originate from luminal progenitor cells, so-called cells of origin. This poses an important and largely unaddressed question: does BRCA1 influence HR repair and genome stability in a cell lineage- and genomic locus-preferred manner? Our preliminary data indicate that BRCA1 modifications signal its timely departure from DSBs and thus effectively neutralize its nuclease-inhibiting activity at DSB. Using clinical samples, we also found that luminal cells from BRCA1 mutation carriers are particularly radiosensitive and prone to accumulation of DSB precursors at specific genomic loci. Based on these compelling preliminary data, we hypothesize that BRCA1 modifications are part of a licensing mechanism that confines the commitment step of HR to S/G2 phase. We further propose that BRCA1 HR repair activity is particularly important for genetic integrity at luminal genes in luminal cells of the breast tissue. Our multidisciplinary team of laboratory and clinician scientists will combine cell culture systems with mouse genetics and human samples to test this novel hypothesis. Our proposed work seeks to validate a previously unrecognized role of BRCA1 in licensing the commitment step in HR, thus challenging the current view of BRCA1 merely as a scaffolding protein. Furthermore, by interrogating BRCA1 HR function in the clinically relevant cell lineage and genomic regions, our work represents a significant departure from traditional cell line-focused mechanistic studies. Our proposed work helps fill a critical knowledge gap between mechanistic investigation of BRCA1 and etiology of tissue/cell lineage-specific BRCA1-associated tumor development, thus substantially advancing BRCA1-related breast cancer research.

Public Health Relevance

By combining cell culture models, mouse genetics, and clinical samples, this multidisciplinary team is poised to illuminate BRCA1 DNA repair function in clinically relevant tissue and genomic contexts. The proposed work promises to have a far-reaching impact on development of more effective risk-assessment tools and cancer prevention/treatment options for BRCA1 mutation carriers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Oberdoerffer, Philipp
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George Washington University
Anatomy/Cell Biology
Schools of Medicine
United States
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