R-loop functions in Brca1-associated mammary tumorigenesis.
Proc Natl Acad Sci U S A
; 121(33): e2403600121, 2024 Aug 13.
Article
in En
| MEDLINE
| ID: mdl-39116124
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
BRCA1 Protein
/
Carcinogenesis
/
R-Loop Structures
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2024
Document type:
Article