Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation.

Autor: He Z; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Ghorayeb R; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Tan S; Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada.; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Chen K; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Lorentzian AC; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Bottyan J; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Aalam SMM; Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Pujana MA; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain., Lange PF; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, Vancouver, British Columbia, Canada., Kannan N; Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA., Eaves CJ; Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada.; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.; School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada., Maxwell CA; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. cmaxwell@bcchr.ubc.ca.; Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, Vancouver, British Columbia, Canada. cmaxwell@bcchr.ubc.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 22; Vol. 13 (1), pp. 2200. Date of Electronic Publication: 2022 Apr 22.
DOI: 10.1038/s41467-022-29885-2
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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