Targets of vitamin D receptor signaling in the mammary gland.

Since the discovery of the vitamin D receptor (VDR) in mammary cells, the role of the vitamin D signaling pathway in normal glandular function and in breast cancer has been extensively explored. In vitro studies have shown that the VDR ligand, 1,25-dihydroxyvitamin D (1,25D), modulates key proteins involved in signaling proliferation, differentiation, and survival of normal mammary epithelial cells. Similar anti-proliferative and pro-differentiating effects of 1,25D have been observed in VDR-positive breast cancer cells, indicating that transformation per se does not abolish vitamin D signaling. However, many transformed breast cancer lose sensitivity to 1,25D secondary to alterations in vitamin D metabolizing enzymes or downregulation of VDR function. Over the years, our laboratory has focused on three general areas: (1) defining mechanisms of vitamin D-mediated apoptosis in breast cancer cells, (2) examining changes in the vitamin D signaling pathway during transformation, including the development of vitamin D resistance, and (3) using mouse models to study the impact of the VDR on growth regulatory pathways in the context of development and tumorigenesis in vivo. Recent developments include detection of megalin-mediated uptake of vitamin D-binding protein (DBP) and identification of CYP27B1 and CYP24 metabolizing enzymes in mammary cells, demonstration of precocious mammary gland development in VDR-null mice, and identification of novel pathways triggered by 1,25D during apoptosis. Our preclinical studies have been complemented by emerging data from other groups suggesting that human breast cancer may be influenced by VDR genotype and vitamin D status. Collectively, these studies have reinforced the need to further define the regulation and function of the vitamin D pathway in cells in relation to prevention and treatment of breast cancer.