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bioRxiv · 10.1101/2024.02.14.580374

R-Loop Functions in Brca1-Associated Mammary Tumorigenesis

Chiang, H.-C.·Qi, L.·Mitra, P.·Hu, Y.·Li, R.
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Abstract

Excessive R-loops, a DNA-RNA hybrid structure, are associated with genome instability and BRCA1 mutation-related breast cancer. Yet the causality of R-loops in tumorigenesis remains unclear. Here we show that R-loop removal by Rnaseh1 overexpression (Rh1-OE) in Brca1-knockout (BKO) mouse mammary epithelium exacerbates DNA replication stress without affecting homology-directed DNA repair. R-loop removal also diminishes luminal progenitors, the cell of origin for estrogen receptor (ER)-negative BKO tumors. However, R-loop reduction does not dampen spontaneous BKO tumor incidence. Rather, it gives rise to a significant percentage of ER-expressing BKO tumors. Thus, R-loops reshape mammary tumor subtype rather than promoting tumorigenesis.

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Chiang, H.-C., Qi, L., Mitra, P., Hu, Y., Li, R.. 2024-02-16. R-Loop Functions in Brca1-Associated Mammary Tumorigenesis. https://doi.org/10.1101/2024.02.14.580374

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