title: Molecular Mechanism Linking BRCA1 Dysfunction to High Grade Serous Epithelial Ovarian Cancers with Peritoneal Permeability and Ascites.
abstract: Ovarian cancer constitutes the second most common gynecological cancer with a five-year survival rate of 40%. Among the various histotypes associated with hereditary ovarian cancer, high-grade serous epithelial ovarian carcinoma (HGSEOC) is the most predominant and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. HGSEOC is a challenge for clinical oncologists, due to late presentation of patient, diagnosis and high rate of relapse. Ovarian tumors have a wide range of clinical presentations including development of ascites as a result of deregulated endothelial function thereby causing increased vascular permeability of peritoneal vessels. The molecular mechanisms remain elusive. Studies have shown that fallopian tube cancers develop in women with BRCA1 gene mutations more often than previously suspected. Recent studies suggest that many primary peritoneal cancers and some high-grade serous epithelial ovarian carcinomas actually start in the fallopian tubes. In this article we have addressed the molecular pathway of a recently identified potential biomarker Ubc9 whose deregulated expression due to BRCA1 dysfunction can result in HGSEOC with peritoneal permeability and formation of ascites. We also discuss the role of downstream targets Caveolin-1 and Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of ascites in ovarian carcinomas. Finally we hypothesize a signaling axis between Ubc9 over expression, loss of Caveolin-1 and induction of VEGF in BRCA1 mutant HGSEOC cells. We suggest that Ubc9-mediated stimulation of VEGF as a novel mechanism underlying ovarian cancer aggressiveness and ascites formation. Agents that target Ubc9 and VEGF signaling may represent a novel therapeutic strategy to impede peritoneal growth and spread of HGSEOC.
authors.affiliation: Cancer Biology Program, Department of OB/GYN, School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
authors.forename: A
authors.initials: A
authors.lastname: Desai
authors.affiliation: Department of Internal Medicine, School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Surgery, Morehouse, School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, USA.
authors.forename: K
authors.initials: K
authors.lastname: Aysola
authors.affiliation: Department of Internal Medicine, University of Buffalo, Erie County Medical Center, Buffalo NY.
authors.forename: O
authors.initials: O
authors.lastname: Akinbobuyi
authors.affiliation: Philadelphia College of Osteopathic Medicine, Suwanee GA.
authors.forename: M
authors.initials: M
authors.lastname: White
authors.affiliation: Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: V E
authors.initials: VE
authors.lastname: Reddy
authors.forename: J
authors.initials: J
authors.lastname: Okoli
authors.forename: C
authors.initials: C
authors.lastname: Clark
authors.forename: E E
authors.initials: EE
authors.lastname: Partridge
authors.forename: Ed
authors.initials: E
authors.lastname: Childs
authors.forename: D J
authors.initials: DJ
authors.lastname: Beech
authors.forename: M V
authors.initials: MV
authors.lastname: Rice
authors.forename: Esp
authors.initials: E
authors.lastname: Reddy
authors.forename: V N
authors.initials: VN
authors.lastname: Rao
keywords: Ascites; BRCA1; BRCA1a; Caveolin-1; Endothelial function; Fallopian tubes; High Grade Serous Epithelial Ovarian Cancer; Peritoneum; Tumor suppression; Ubc9; VEGF