PDF(Pubmed)
Abstract：
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 α negative (ERα-) 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 ERα 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.
摘要：
R环的有害积累，DNA-RNA杂交结构,导致基因组不稳定。它们与BRCA1突变相关的乳腺癌有关，源自腔祖细胞的雌激素受体α阴性（ERα-）肿瘤类型。然而,在体内尚未确定R环在肿瘤发生中的因果关系。这里,我们在体内过表达小鼠Rnaseh1（Rh1-OE），以去除Brca1缺陷小鼠乳腺上皮（BKO）中积累的R环。R环去除会加剧增殖的BKO乳腺上皮细胞的DNA复制应激，对电离辐射后的双链断裂的同源定向修复几乎没有影响。与BKO同行相比，BKO-Rh1-OE乳腺含有较少的腔祖细胞，但较成熟的腔细胞。尽管在BKO和BKO-Rh1-OE小鼠中自发性乳腺肿瘤的发生率相似，相当比例的BKO-Rh1-OE肿瘤表达ERα和孕激素受体。我们的结果表明，不是直接提高整体肿瘤发病率，R环通过塑造Brca1肿瘤的起源细胞来影响乳腺肿瘤亚型。
