Abstract ES12-2: Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis

Abstract

Abstract Breast cancer risk is significantly elevated for women who carry germ-line mutations in the tumor suppressor gene BRCA1. BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. These precancerous cells of origin are defective in luminal differentiation in BRCA1 mutation carriers before any clinical evidence of cancer. While BRCA1 is best known for its functions in double strand break DNA repair and response to DNA replication stress, it is unclear whether loss of these ubiquitously important functions of BRCA1 is sufficient to account for lineage-specific breast tumor development in BRCA1 mutation-carrying women. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention. Recent discoveries from others and us challenge the prevailing DNA repair/replication-centric paradigm. First, in vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Using breast tissue of cancer-free BRCA1 mutation-carrying women, we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1 knockout mouse mammary epithelium. Of note, this BRCA1/COBRA1 interaction occurs in a DSB repair-independent manner. Based on these findings, we suggest that as part of its tumor suppressor activity, BRCA1 promotes luminal epithelial differentiation by mitigating Pol II pausing-dependent transcriptional stress at luminal fate genes. We further propose that accumulation of transcriptional stress in BRCA1-deficient luminal cells redirects luminal transcription and alters luminal homeostasis, which ultimately contributes to lineage-specific BRCA1-associated tumorigenesis. Citation Format: Li R. Link between BRCA1 and Pol II pausing in mammary gland development and tumorigenesis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES12-2.