BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Tejaswita M Karve,Xin Li,Rosie Sneed,Anju Preet,Clara Salamanca,Jingwen Xu,Eliot M Rosen,Tapas Saha,Deepak Kumar,Swati Palit Deb

doi:10.1371/journal.pone.0037697

Abstract

Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells.

Highlights

Ovarian cancer is one of the leading gynecological cancers in the United States with 22,280 estimated new cases and 15,500 deaths in 2012
Most ovarian cancers occur within the ovarian surface epithelium (OSE) and investigations using OSE cells derived from both normal individual and ovarian cancer patients are critical to elucidate the etiology of human ovarian cancer
Generation of SKOV3 sub-cell lines with stable breast cancer susceptibility gene 1 (BRCA1) expression would further assist in understanding the effect of BRCA1 in human ovarian carcinoma

Summary

Introduction

Ovarian cancer is one of the leading gynecological cancers in the United States with 22,280 estimated new cases and 15,500 deaths in 2012 (http://www.cancer.gov/cancertopics/types/ ovarian; Assessed on February, 2012). Detection of ovarian cancer is shown significantly increase patient life expectancy to as high as 85% [1]. There is a need to develop biomarkers that can be helpful in detecting ovarian cancer in early stages of the disease. Only 5–10% of women with ovarian cancer have inherited genetic mutations in tumor suppressor genes such as BRCA1 and BRCA2 that predisposes them to breast and ovarian cancer [2,3,4]. A genetic linkage cohort study consisting of 214 breast cancer and breast-ovary cancer families combined, revealed that 90% of the patients harbored mutations in their BRCA1 gene [5]. BRCA1 mutation(s) carrier females have about 15 fold greater risk for developing ovarian cancer when compared to their non-carrier female counterparts [6,7]

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Conclusion