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 () and Mona Shehata ()
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Maryam Ghaderi Najafabadi: University of Cambridge
G. Kenneth Gray: Harvard Medical School (HMS)
Li Ren Kong: University of Cambridge
Komal Gupta: University of Cambridge
David Perera: University of Cambridge
Huw Naylor: University of Cambridge
Joan S. Brugge: Harvard Medical School (HMS)
Ashok R. Venkitaraman: University of Cambridge
Mona Shehata: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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 Brca2mut/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.

Date: 2023
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DOI: 10.1038/s41467-023-40956-w

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