Abstract
BackgroundBRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics in breast epithelial cells.MethodsH3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+). Non-tumorigenic MCF10A breast epithelial cells with engineered BRCA1 haploinsufficiency were used to confirm the H3K27ac changes. The impact of BRCA1 mutations on enhancer function and enhancer-promoter looping was assessed in MCF10A cells.ResultsHere, we show that primary mammary epithelial cells from women with BRCA1 mutations display significant loss of H3K27ac-associated super-enhancers. These BRCA1-dependent super-enhancers are enriched with binding motifs for the GATA family. Non-tumorigenic BRCA1mut/+ MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1mut/+ MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1mut/+ MCF10A cells.ConclusionsH3K27ac-associated super-enhancer loss is a previously unappreciated functional deficiency in ostensibly normal BRCA1 mutation-carrying breast epithelium. Our findings offer new mechanistic insights into BRCA1 mutation-associated transcriptional and epigenetic abnormality in breast epithelial cells and tissue/cell lineage-specific tumorigenesis.
Highlights
BRCA1-associated breast cancer originates from luminal progenitor cells
BRCA1mut/+ Human mammary epithelial cell (HMEC) are associated with reduced superenhancer mark To compare super-enhancer landscapes in BRCA1+/+ and BRCA1mut/+ normal human breast epithelia, primary HMECs were isolated from fresh cancer-free breast tissues of BRCA1 mutation carriers (BRCA1mut/+, n = 3) and non-carriers (BRCA1+/+, n = 3), who underwent prophylactic mastectomy and reduction mammoplasty, respectively
A total of 343 super-enhancers were identified in BRCA1mut/+ and/or BRCA1+/+ breast epithelia, 268 of which were shared by BRCA1+/+ and BRCA1mut/+ HMECs (Additional file 2: Table S1, for an example see Additional file 3: Figure S1)
Summary
BRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. 1 in 400 women in the USA carry germline BRCA1 mutation (BRCA1mut/+) [1, 2]. These BRCA1 mutation carriers have significantly higher risk of developing breast cancer compared to the general population, with an estimated cumulative risk of 65% by the age of 70 [3, 4]. The only effective risk-reducing options for women with BRCA1 mutations are prophylactic mastectomy and oophorectomy, which can achieve 90% and 50% reduction in breast cancer risk, respectively [6,7,8,9]. Understanding functional deficiency that occurs prior to clinically evident cancer in precancerous BRCA1mut/+ breast epithelium is an important step towards developing alternative preventive strategies with higher precision and fewer side effects
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