| First Author | Najafabadi MG | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 5206 |
| PubMed ID | 37626143 | Mgi Jnum | J:339675 |
| Mgi Id | MGI:7523664 | Doi | 10.1038/s41467-023-40956-w |
| Citation | Najafabadi MG, et al. (2023) A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells. Nat Commun 14(1):5206 |
| abstractText | 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 Brca2(mut/WT) luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses reveal comparable epithelial compositions among wildtype and Brca2(mut/WT) mammary glands, Brca2(mut/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 Brca2(mut/WT) HR- luminal cell expansion. Our findings indicate that Brca2(mut/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. |
