CROSSTALK BETWEEN BRCA1 AND TRANSCRIPTION IN BREAST CANCER

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 sufficientto account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnectcould inform more effective risk assessment and disease prevention. Our mouse genetics work identifiedunexpected functional antagonism between BRCA1 and COBRA1, a dedicated transcription elongation factorimportant for luminal gene transcription. This BRCA1/COBRA1 crosstalk regulates luminal progenitor function,luminal transcription-related DSB precursors, and mammary tumorigenesis in a DSB repair-independentmanner. In a parallel investigation using clinical samples, we found that cancer-free BRCA1 mutation carriersaccumulate DSB precursors specifically in their breast luminal epithelial cells. Based on this groundwork, wehypothesize that, through its crosstalk with COBRA1-dependent transcription elongation machinery,BRCA1 prevents preferential accumulation of DSB precursors at luminal genes and thus reducesgenome instability in luminal cell compartment. We will use mouse genetics and clinical samples toelucidate the impact of BRCA1/COBRA1 antagonism on luminal homeostasis, DSB precursor production, andbreast tumorigenesis. The concept to be validated in our proposed work clearly departs from the prevailingDNA repair-centric paradigm. Furthermore, the DNA repair-independent BRCA1/COBRA1 antagonism pointsto a previously unappreciated direction for elucidating BRCA1 tumor suppressor function and preventingBRCA1-associated breast cancer. When successfully executed, our studies promises to lay a solid conceptualfoundation to reconcile an enduring disconnect concerning BRCA1-associated breast cancer, thus catapultingunderstanding of BRCA1 cancer biology to a new level.