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.

Comparing Characteristics of Pelvic High-grade Serous Carcinomas with and without Breast Cancer Gene Variants on MR Imaging

“…The fact that significant differences were observed only for Max enhancement and area under curve, but not for Max Rel enhancement, is assumed to be due to the large variation in data for BRCA1 variant-positive HGSCs in Max Rel enhancement and the small number of BRCA variant-positive HGSCs. 23 , 24 …”

A Hypothetical Molecular Mechanism Linking Loss of BRCA1 Function to Infertility

“…In our previous work, we first proposed a novel Ubc9 -Caveolin-1-VEGF-SIRT1-ER-a axis that is facilitated by functional BRCA1 [19]. When BRCA1 is mutated, this axis is disturbed, and it results in TNBC with epithelial to mesenchymal transition that allows for metastasis to the lungs [20].…”