Nature Communications (Aug 2023)

A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells

  • Maryam Ghaderi Najafabadi,
  • G. Kenneth Gray,
  • Li Ren Kong,
  • Komal Gupta,
  • David Perera,
  • Huw Naylor,
  • Joan S. Brugge,
  • Ashok R. Venkitaraman,
  • Mona Shehata

DOI
https://doi.org/10.1038/s41467-023-40956-w
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 17

Abstract

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Abstract Germline BRCA2 mutation carriers frequently develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that monoallelic Brca2 mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2mut/WT luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses reveal comparable epithelial compositions among wildtype and Brca2mut/WT mammary glands, Brca2mut/WT HR- luminal cells exhibit greater organoid formation and preferentially survive and expand under replication stress. ScRNA-seq analysis corroborates the expansion of HR- luminal cells which express elevated transcript levels of Tetraspanin-8 (Tspan8) and Thrsp, plus pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevents Brca2mut/WT HR- luminal cell expansion. Our findings indicate that Brca2mut/WT cells activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.