We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells.
- Authors
Najafabadi, Maryam Ghaderi; Gray, G. Kenneth; Kong, Li Ren; Gupta, Komal; Perera, David; Naylor, Huw; Brugge, Joan S.; Venkitaraman, Ashok R.; Shehata, Mona
- 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. Here the authors study how BRCA2 mutations affect mammary epithelial subpopulations. They report that Brca2mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2mut/WT HR- luminal cells.
- Subjects
EPITHELIAL cells; TYPE I interferons; HORMONE receptors; MAMMARY glands; BRCA genes; NUCLEAR receptors (Biochemistry); BREAST
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40956-w