Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation.
Zhengcheng HeRyan GhorayebSusanna TanKe ChenAmanda C LorentzianJack BottyanSyed Mohammed Musheer AalamMiguel Angel PujanaPhilipp F LangeNagarajan KannanConnie J EavesChristopher A MaxwellPublished in: Nature communications (2022)
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.
Keyphrases
- induced apoptosis
- breast cancer risk
- endothelial cells
- dna damage
- cell cycle arrest
- single cell
- oxidative stress
- cell therapy
- poor prognosis
- dna methylation
- cell death
- adipose tissue
- wild type
- induced pluripotent stem cells
- type diabetes
- metabolic syndrome
- long non coding rna
- copy number
- cell proliferation
- cell cycle
- pi k akt
- skeletal muscle
- pluripotent stem cells