TY - JOUR
T1 - Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation
AU - He, Zhengcheng
AU - Ghorayeb, Ryan
AU - Tan, Susanna
AU - Chen, Ke
AU - Lorentzian, Amanda C.
AU - Bottyan, Jack
AU - Aalam, Syed Mohammed Musheer
AU - Pujana, Miguel Angel
AU - Lange, Philipp F.
AU - Kannan, Nagarajan
AU - Eaves, Connie J.
AU - Maxwell, Christopher A.
N1 - Funding Information:
We thank Dr. John Stingl for assistance with the mouse organoid cultures and helpful discussions. We thank Dr. Martin Hirst for assistance with the analysis of rs138974428 and PLK1 enhancer in mammary epithelial subpopulations. We thank the BCAC and CIMBA consortia for making the summary statistics of genome-wide association studies available to the public. This study was partially funded by the Canadian Institutes of Health Research (CIHR 169111 and CIHR CEEHRC Phase II EP2-120591), the Canadian Cancer Research Institute (CCSRI 21296), the Canadian Cancer Society (BC-RG-16), the Michael Cuccione Foundation for Childhood Cancer Research, and the BC Children’s Hospital Research Institute. Z.H. and A.L. received University of British Columbia Four Year Doctoral Fellowships. N.K. was supported partly through Eagles Foundation Rochester Minnesota and Mayo Clinic Breast Cancer SPORE (CA116201-12CEP). S.T. received a CIHR Banting and Best Doctoral Studentship. The CIMBA data management and data analysis were supported by funders as listed 72 ,73.
Funding Information:
We thank Dr. John Stingl for assistance with the mouse organoid cultures and helpful discussions. We thank Dr. Martin Hirst for assistance with the analysis of rs138974428 and PLK1 enhancer in mammary epithelial subpopulations. We thank the BCAC and CIMBA consortia for making the summary statistics of genome-wide association studies available to the public. This study was partially funded by the Canadian Institutes of Health Research (CIHR 169111 and CIHR CEEHRC Phase II EP2-120591), the Canadian Cancer Research Institute (CCSRI 21296), the Canadian Cancer Society (BC-RG-16), the Michael Cuccione Foundation for Childhood Cancer Research, and the BC Children’s Hospital Research Institute. Z.H. and A.L. received University of British Columbia Four Year Doctoral Fellowships. N.K. was supported partly through Eagles Foundation Rochester Minnesota and Mayo Clinic Breast Cancer SPORE (CA116201-12CEP). S.T. received a CIHR Banting and Best Doctoral Studentship. The CIMBA data management and data analysis were supported by funders as listed. ,
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-29885-2
DO - 10.1038/s41467-022-29885-2
M3 - Article
C2 - 35459234
AN - SCOPUS:85128782254
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2200
ER -