BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells
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Zhengcheng He1,*, Nagarajan Kannan2,3,* Oksana Nemirovsky1, Helen Chen1, Marisa Connell1, Brian Taylor4, Jihong Jiang1, Linda M. Pilarski4, Markus C. Fleisch5, Dieter Niederacher6, Miguel Angel Pujana7, Connie J. Eaves2,8 and Christopher A. Maxwell1,9
1 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
2 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
3 Department of Laboratory Medicine and Pathology, Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
4 Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada
5 Department of Obstetrics and Gynaecology, Landesfrauenklinik, HELIOS University Medical Center, Wuppertal, Germany
6 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Germany
7 Breast Cancer and Systems Biology Unit, Program Against Cancer Therapeutic Resistance (ProCure), Catalan Institute of Oncology, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
8 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
9 Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital, Vancouver, British Columbia, Canada
* These authors have contributed equally to this work
Christopher A. Maxwell, email:
Connie J. Eaves, email:
Keywords: BRCA1, spindle orientation, mitotic instability, human mammary epithelial cells
Received: February 08, 2017 Accepted: February 16, 2017 Published: February 25, 2017
BRCA1 deficiency may perturb the differentiation hierarchy present in the normal mammary gland and is associated with the genesis of breast cancers that are genomically unstable and typically display a basal-like transcriptome. Oriented cell division is a mechanism known to regulate cell fates and to restrict tumor formation. We now show that the cell division axis is altered following shRNA-mediated BRCA1 depletion in immortalized but non-tumorigenic, or freshly isolated normal human mammary cells with graded consequences in progeny cells that include aneuploidy, perturbation of cell polarity in spheroid cultures, and a selective loss of cells with luminal features. BRCA1 depletion stabilizes HMMR abundance and disrupts cortical asymmetry of NUMA-dynein complexes in dividing cells such that polarity cues provided by cell-matrix adhesions were not able to orient division. We also show that immortalized mammary cells carrying a mutant BRCA1 allele (BRCA1 185delAG/+) reproduce many of these effects but in this model, oriented divisions were maintained through cues provided by CDH1+ cell-cell junctions. These findings reveal a previously unknown effect of BRCA1 suppression on mechanisms that regulate the cell division axis in proliferating, non-transformed human mammary epithelial cells and consequent downstream effects on the mitotic integrity and phenotype control of their progeny.
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