Association between vitamin D and ovarian cancer development in BRCA1 mutation carriers.

Tanja Pejovic,Sonali Joshi,Sarah Thisted,Shawn Campbell,Fuhua Xu,Jing Xu

doi:10.18632/oncotarget.27803

Tanja Pejovic, Sonali Joshi + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.27803

Copy DOI

Abstract

Objective: Women with inherited mutations in BRCA1 gene have a high (40–70%) genetic risk of developing ovarian cancer. Epidemiological studies suggest an inverse correlation between serum vitamin D (VD) levels and the risk of ovarian cancer, but there is a lack of data from BRCA1 mutation (BRCA1mut) carriers. Therefore, we investigated VD levels and actions in cancer free women with BRCA1 mutations.Materials and Methods: Blood, ovary and fallopian tube samples were collected from healthy pre-menopausal women with BRCA1mut and without BRCA1 mutations (BRCAwt). Serum calcifediol (major circulating form of VD) concentrations were measured by electrochemiluminescence immunoassay. Immunohistochemistry was performed on paraffin-embedded ovarian and fallopian tube sections to determine vitamin D receptor (VDR) expression. Ovarian surface epithelial cells (OSEs) from BRCA1mut carriers were cultured with or without calcitriol supplementation for 72 hrs. VDR protein levels, cell proliferation and cell viability were analyzed.Results: BRCA1mut women had lower serum calcifediol levels compared to BRCAwt women (p = 0.003). VDR protein expression was evident in ovarian and the fallopian tube epithelium of BRCAwt patients, but was reduced in BRCA1mut women. Calcitriol (biologically active VD) supplementation elevated VDR expression in cultured BRCA1mut OSEs (p = 0.005) and decreased cell proliferation rates in a dose-dependent manner without inducing apoptosis.Conclusions: VD biosynthesis and signaling via VDR in the ovarian and fallopian tube epithelium are impaired in BRCA1mut women. VD treatment may limit BRCA1mut epithelial cell proliferation without affecting cell viability, providing a rationale for exploring the potential for VD in ovarian cancer prevention in BRCA1mut carriers.

Highlights

Epithelial ovarian cancer (EOC) is a lethal disease with 5-year survival rates of 40% [1]
vitamin D (VD) biosynthesis and signaling via vitamin D receptor (VDR) in the ovarian and fallopian tube epithelium are impaired in BRCA1mut women
Considering the regulatory effects of VD on cell proliferation, we investigated the potential for VD in the prevention of EOC in BRCA1mut carriers

Summary

Introduction

Epithelial ovarian cancer (EOC) is a lethal disease with 5-year survival rates of 40% [1]. 15% of EOC patients are diagnosed with Stage I disease and have favorable 5 year survival rate of 92% [2]. Women at a high risk for EOC are offered regular pelvic exams in combination with transvaginal ultrasound and a blood test for CA-125 tumor marker, but these strategies have failed to significantly improve patient survival [3]. Developing strategies to identify women with a high risk of developing EOC and to prevent tumor development is critical for reducing EOC-related mortality. Based on a cumulative EOC risk of 0.55% to age 35 for BRCA1mut carriers, an international registry study recommended bilateral salpingo-oophorectomy before age 40 to maximize prevention and to minimize adverse effects [12]. There is an urgent need to develop other noninvasive and cost-effective methods to prevent EOC, in young women carrying BRCA1mut

Methods

Results

Conclusion