Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada.
Nat Commun. 2022 Apr 22;13(1):2200. doi: 10.1038/s41467-022-29885-2.
Preneoplastic mammary tissues from human female BRCA1 mutation carriers, or Brca1-mutant mice, display unexplained abnormalities in luminal differentiation. We now study the division characteristics of human mammary cells purified from female BRCA1 mutation carriers or non-carrier donors. We show primary BRCA1 mutant/+ cells exhibit defective BRCA1 localization, high radiosensitivity and an accelerated entry into cell division, but fail to orient their cell division axis. We also analyse 15 genetically-edited BRCA1 mutant/+ human mammary cell-lines and find that cells carrying pathogenic BRCA1 mutations acquire an analogous defect in their division axis accompanied by deficient expression of features of mature luminal cells. Importantly, these alterations are independent of accumulated DNA damage, and specifically dependent on elevated PLK1 activity induced by reduced BRCA1 function. This essential PLK1-mediated role of BRCA1 in controlling the cell division axis provides insight into the phenotypes expressed during BRCA1 tumorigenesis.
来自携带人源 BRCA1 基因突变的女性或 Brca1 突变小鼠的癌前乳腺组织表现出管腔分化中无法解释的异常。我们现在研究从携带 BRCA1 基因突变的女性或非携带者供体中纯化的人乳腺细胞的分裂特征。我们发现原发性 BRCA1 突变体/+细胞表现出 BRCA1 定位缺陷、高放射敏感性和加速进入细胞分裂，但无法确定其细胞分裂轴。我们还分析了 15 种经过基因编辑的 BRCA1 突变体/+人乳腺细胞系，发现携带致病性 BRCA1 突变的细胞在其分裂轴上获得类似的缺陷，同时成熟管腔细胞的特征表达也不足。重要的是，这些改变不依赖于累积的 DNA 损伤，而是特异性地依赖于由 BRCA1 功能降低引起的 PLK1 活性升高。BRCA1 在控制细胞分裂轴中的这个必需的 PLK1 介导作用，为 BRCA1 肿瘤发生过程中表达的表型提供了深入的了解。
