BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells.
Women who carry a germline mutation in BRCA1 gene typically develop triple negative breast cancers (TNBC) and high grade serous ovarian cancers (HGSOC). Previously, we reported that wild type BRCA1 proteins, unlike the disease-associated mutant BRCA1 proteins to bind the sole sumo E2-conjugating enzyme Ubc9. In this study, we have used clinically relevant cell lines with known BRCA1 mutations and report thein-vivoassociation of BRCA1 and Ubc9 in normal mammary epithelial cells but not in BRCA1 mutant HGSOC and TNBC cells by immunofluorescence analysis. BRCA1-mutant HGSOC/TNBC cells and ovarian tumor tissues showed increased expression of Ubc9 compared to BRCA1 reconstituted HGSOC, normal mammary epithelial cells and matched normal ovarian tissues. Knockdown of Ubc9 expression resulted in decreased proliferation and migration of BRCA1 mutant TNBC and HGSOC cells. This is the first study demonstrating the functional link between BRCA1 mutation, high Ubc9 expression and increased migration of HGSOC and TNBC cells. High Ubc9 expression due to BRCA1 mutation may trigger an early growth and transformation advantage to normal breast and ovarian epithelial cells resulting in aggressive cancers. Future work will focus on studying whether Ubc9 expression could show a positive correlation with BRCA1 linked HGSOC and basal like TNBC phenotype.
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Xu
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Footman
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Qin
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Aysola
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Black
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Reddy
Department of Pathology, University of Alabama at Birmingham, Birmingham, USA.
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Singh
Department of Pathology, University of Alabama at Birmingham, Birmingham, USA.
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Grizzle
VA Medical Center, Emory University School of Medicine, Georgia.
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You
Department of Nutrition, University of Alabama at Birmingham, Birmingham, USA.
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Moellering
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Reddy
Department of Nutrition, University of Alabama at Birmingham, Birmingham, USA.
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Fu
Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
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Rao
BRCA1; BRCA1a; Migration; Proliferation; Protein-Protein Interaction; Serous Epithelial Ovarian Cancers; Triple Negative Breast Cancers; Ubc9