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

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 (BRCA1^mut) 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 BRCA1^mut and without BRCA1 mutations (BRCA^wt). 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 BRCA1^mut carriers were cultured with or without calcitriol supplementation for 72 hrs. VDR protein levels, cell proliferation and cell viability were analyzed.

Results: BRCA1^mut women had lower serum calcifediol levels compared to BRCA^wt women (p = 0.003). VDR protein expression was evident in ovarian and the fallopian tube epithelium of BRCA^wt patients, but was reduced in BRCA1^mut women. Calcitriol (biologically active VD) supplementation elevated VDR expression in cultured BRCA1^mut 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 BRCA1^mut women. VD treatment may limit BRCA1^mut epithelial cell proliferation without affecting cell viability, providing a rationale for exploring the potential for VD in ovarian cancer prevention in BRCA1^mut carriers.