Most BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. BRCA1 plays important roles in double strand break (DSB) repair and response to DNA replication stress. However, it remains a conundrum as to whether these ubiquitously important functions of BRCA1 are sufficient to account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention. Our mouse genetics work identified unexpected functional antagonism between BRCA1 and COBRA1, a dedicated transcription elongation factor important for luminal gene transcription. This BRCA1/COBRA1 crosstalk regulates luminal progenitor function, luminal transcription-related DSB precursors, and mammary tumorigenesis in a DSB repair-independent manner. In a parallel investigation using clinical samples, we found that cancer-free BRCA1 mutation carriers accumulate DSB precursors specifically in their breast luminal epithelial cells. Based on this groundwork, we hypothesize that, through its crosstalk with COBRA1-dependent transcription elongation machinery, BRCA1 prevents preferential accumulation of DSB precursors at luminal genes and thus reduces genome instability in luminal cell compartment. We will use mouse genetics and clinical samples to elucidate the impact of BRCA1/COBRA1 antagonism on luminal homeostasis, DSB precursor production, and breast tumorigenesis. The concept to be validated in our proposed work clearly departs from the prevailing DNA repair-centric paradigm. Furthermore, the DNA repair-independent BRCA1/COBRA1 antagonism points to a previously unappreciated direction for elucidating BRCA1 tumor suppressor function and preventing BRCA1-associated breast cancer. When successfully executed, our studies promises to lay a solid conceptual foundation to reconcile an enduring disconnect concerning BRCA1-associated breast cancer, thus catapulting understanding of BRCA1 cancer biology to a new level.
By combining the awesome power of mouse genetics, precious clinical samples, and cutting-edge technologies, this multidisciplinary team is poised to illuminate a DNA repair-independent function of BRCA1 in breast cancer suppression. 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.
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