Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation

Zhengcheng He, Ryan Ghorayeb, Susanna Tan, Ke Chen, Amanda C. Lorentzian, Jack Bottyan, Syed Mohammed Musheer Aalam, Miguel Angel Pujana, Philipp F. Lange, Nagarajan Kannan, Connie J. Eaves and Christopher A. Maxwell ()
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Zhengcheng He: University of British Columbia
Ryan Ghorayeb: University of British Columbia
Susanna Tan: Terry Fox Laboratory, British Columbia Cancer Research Institute
Ke Chen: University of British Columbia
Amanda C. Lorentzian: University of British Columbia
Jack Bottyan: University of British Columbia
Syed Mohammed Musheer Aalam: Department of Laboratory Medicine and Pathology, Mayo Clinic
Miguel Angel Pujana: ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Philipp F. Lange: University of British Columbia
Nagarajan Kannan: Department of Laboratory Medicine and Pathology, Mayo Clinic
Connie J. Eaves: Terry Fox Laboratory, British Columbia Cancer Research Institute
Christopher A. Maxwell: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29885-2

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