title: A Novel Pathway that Links Caveolin-1 Down-Regulation to BRCA1 Dysfunction in Serous Epithelial Ovarian Cancer Cells.
abstract: Ovarian cancer is the second most common gynecological cancer and the five-year survival rate is only about 40%. High-grade serous carcinoma is the pre-dominant histotype associated with hereditary ovarian cancer and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. BRCA1 and its isoform BRCA1a are multifunctional proteins that are the most evolutionary conserved of all the other splice variants. Our group has previously reported that BRCA1/1a proteins, unlike K109R and C61G mutants, suppress growth of ovarian cancer cells by tethering Ubc9. In this study we found wild type BRCA1/1a proteins to induce expression of caveolin-1, a tumor suppressor in BRCA1-mutant serous epithelial ovarian cancer (SEOC) cells by immunofluorescence analysis. The K109R and C61G disease associated mutant BRCA1 proteins that do not bind Ubc9 were not as efficient in up-regulation of caveolin-1 expression in SEOC cells. Additionally, immunofluorescence analysis showed BRCA1/1a proteins to induce redistribution of Caveolin-1 from cytoplasm and nucleus to the cell membrane. This is the first study demonstrating the physiological link between loss of Ubc9 binding, loss of growth suppression and loss of Caveolin-1 induction of disease-associated mutant BRCA1 proteins in SEOC cells. Decreased Caveolin-1 expression combined with elevated Ubc9 expression can in the future be used as an early biomarker for BRCA1 mutant SEOC.
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Agyemang
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Aysola
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Giles
authors.affiliation: Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Oprea
authors.affiliation: Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: O'Regan
authors.affiliation: Department of Obstetrics & Gynecology, Division of Gynecological Oncology, 618 20th Street South, University of Alabama at Birmingham, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Partridge
authors.affiliation: Department of Pathology and Medicine, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA 30310, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Harris-Hooker
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Valarie Montgomery
authors.initials: VM
authors.lastname: Rice
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: E Shyam P
authors.initials: ES
authors.lastname: Reddy
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.
authors.forename: Veena N
authors.initials: VN
authors.lastname: Rao
keywords: BRCA1; BRCA1a; Caveolin-1; Protein-protein; Serous Epithelial Ovarian Cancer; Ubc9