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R-loop functions in Brca1-associated mammary tumorigenesis.

Huai-Chin Chiang1, Leilei Qi2, Payal Mitra1

  • 1Department of Biochemistry and Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC 20037.

Proceedings of the National Academy of Sciences of the United States of America
|August 8, 2024
PubMed
Summary
This summary is machine-generated.

R-loops, DNA-RNA structures, contribute to genome instability and BRCA1-related breast cancer. Removing R-loops in BRCA1-deficient cells altered tumor subtypes, suggesting R-loops influence cancer cell of origin.

Keywords:
BRCA1R-loopsmouse geneticstumorigenesis

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • R-loops (DNA-RNA hybrids) are implicated in genome instability.
  • They are associated with BRCA1-mutation-related estrogen receptor-negative breast cancer originating from luminal progenitor cells.
  • The in vivo causality of R-loops in tumorigenesis remains unclear.

Purpose of the Study:

  • To investigate the in vivo role of R-loops in BRCA1-deficient mammary tumorigenesis.
  • To determine how R-loop removal affects DNA replication stress and repair.
  • To analyze the impact of R-loop modulation on mammary tumor subtypes and cell of origin.

Main Methods:

  • Overexpression of mouse Rnaseh1 (Rh1-OE) to reduce R-loops in Brca1-deficient (BKO) mouse mammary epithelium.
  • Assessment of DNA replication stress and homology-directed repair.
  • Analysis of mammary gland cell populations (luminal progenitor vs. mature luminal cells).
  • Monitoring of spontaneous mammary tumor incidence and subtype (ERα and progesterone receptor expression).

Main Results:

  • R-loop removal in BKO cells exacerbated DNA replication stress.
  • Homology-directed repair of double-strand breaks was largely unaffected by R-loop reduction.
  • BKO-Rh1-OE mammary glands showed fewer luminal progenitor cells and more mature luminal cells compared to BKO.
  • Mammary tumor incidence was similar between BKO and BKO-Rh1-OE, but a significant portion of BKO-Rh1-OE tumors expressed ERα and progesterone receptor.

Conclusions:

  • R-loops do not directly increase overall mammary tumor incidence in a BRCA1-deficient context.
  • R-loop accumulation influences the cell of origin for BRCA1-related mammary tumors.
  • Modulating R-loops can alter the subtype of BRCA1-deficient breast cancer, shifting towards ERα-positive phenotypes.