A Novel Pathway that Links Caveolin-1 Down-Regulation to BRCA1 Dysfunction in Serous Epithelial Ovarian Cancer Cells.

Jingyao Xu,Veena N Rao,Edward E Partridge,Yunlong Qin,Gabriela Oprea,Ruth M O’Regan,E Shyam P Reddy,Valarie Montgomery Rice,Mercedes Giles,Kartik Aysola,Sandra Harris-Hooker,Stephanie Agyemang

doi:10.18650/2376-046x.11004

Jingyao Xu, Veena N Rao + Show 10 more

Open Access

https://doi.org/10.18650/2376-046x.11004

Copy DOI

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.

Highlights

Ovarian cancer is the second most common gynecological cancer and over 95 percent of malignant tumors are of the epithelial type
UWB1.289 is a BRCA1null ovarian cancer cell line obtained from a papillary serous tumor [48]
Immunoflourescence analysis using caveolin-1 antibody revealed low level expression of caveolin-1 in UWB1.289 cells (Figure 2). These results suggest that loss of BRCA1 in UWB1.289 can down regulate caveolin-1 expression similar to what was observed previously in serous ovarian carcinomas [48]

Summary

Introduction

Ovarian cancer is the second most common gynecological cancer and over 95 percent of malignant tumors are of the epithelial type. BRCA1; BRCA1a; Ubc9; Serous Epithelial Ovarian Cancer; Caveolin-1; Protein-protein Our lab has identified and cloned two major isoforms of BRCA1, namely BRCA1a/p110 and BRCA1b/p100 [9,10], which are the most evolutionary conserved of all the isoforms and expressed at reduced levels in ovarian cancers compared to normal cells [11,12,13,14].

Results

Conclusion