Germline BRCA2基因突变携带者常常发展为乳腺癌，但BRCA2突变如何影响乳腺上皮亚群体尚不明确。在这里，我们报道了在复制应激条件下经历单等位Brca2mut/WT乳腺小器官的转录反应，该反应选择性地扩张缺乏激素受体表达（HR-）的Brca2mut/WT乳腺内皮细胞。 CyTOF分析显示野生型和Brca2mut/WT乳腺腺体具有可比较的上皮组成，但Brca2mut/WT HR-乳腺内皮细胞在复制应激下具有更大的小器官形成能力，并且在复制应激条件下选择性地存活和扩张。单细胞RNA测序分析证实了HR-乳腺内皮细胞的扩张，这些细胞表达Tetraspanin-8 (Tspan8)和Thrsp的转录水平升高，以及与复制应激生存有关的途径，包括I型干扰素反应。值得注意的是，CRISPR/Cas9介导的Tspan8或Thrsp的缺失阻止了Brca2mut/WT HR-乳腺内皮细胞的扩张。我们的发现表明，Brca2mut/WT细胞在复制应激后激活了转录反应，通过干扰素反应和乳腺小泡基因的表达，有选择性地促进了HR-乳腺内皮细胞的扩张。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.