R- loop functions in Brca1-associated mammary tumorigenesis

• 成果类型: Article
• 署名作者: Chiang, Huai - Chin; Qi, Leilei; Mitra, Payal; Huang, Yimeng; Hu, Yanfen; Li, Rong
• 署名单位: George Washington University; George Washington University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9298
• DOI: 10.1073/pnas.2403600121
• 发表日期: 2024-08-13
• 关键词: genome integrity; breast-cancer; brca1; dna; Mutation; transcription; RECRUITMENT; progenitors; reveals; threats

摘要

Deleterious accumulation of R- loops, a DNA-RNA hybrid structure, contributes to genome instability. They are associated with BRCA1 mutation- related breast cancer, an estrogen receptor alpha negative (ER alpha-) tumor type originating from luminal progenitor cells. However, a presumed causality of R- loops in tumorigenesis has not been established in vivo. Here, we overexpress mouse Rnaseh1 (Rh1-OE) in vivo to remove accumulated R- loops in Brca1- deficient mouse mammary epithelium (BKO). R- loop removal exacerbates DNA replication stress in proliferating BKO mammary epithelial cells, with little effect on homology- directed repair of double- strand breaks following ionizing radiation. Compared to their BKO counterparts, BKO- Rh1-OE mammary glands contain fewer luminal progenitor cells but more mature luminal cells. Despite a similar incidence of spontaneous mammary tumors in BKO and BKO- Rh1-OE mice, a significant percentage of BKO-Rh1-OE tumors express ER alpha and progesterone receptor. Our results suggest that rather than directly elevating the overall tumor incidence, R- loops influence the mammary tumor subtype by shaping the cell of origin for Brca1 tumors.