The effect of vitamin D3 receptor ablation on mammary gland development and tumorigenesis

The biologically active form of vitamin D₃, 1α,25 Dihydroxyvitamin D₃ (1,25D₃), is a steroid hormone that mediates effects on calcium homeostasis through the nuclear vitamin D ₃ receptor (VDR). 1,25D₃ inhibits growth of estrogen-dependent and estrogen-independent breast tumor cells and the VDR is present in over 80% of breast tumors, making the vitamin D₃ signaling pathway an attractive target for treatment of early and late stage breast cancers. Additionally, 1,25D₃ inhibits the development of carcinogen induced mammary tumors, but the role of the VDR in normal mammary gland development is unknown.; To gain additional insight into the coupling of the VDR to growth regulatory pathways in mammary cells, VDR knockout (KO) and wild type (WT) mice were utilized to assess the role of the VDR during puberty, pregnancy, lactation and involution. To investigate the role of VDR on tumorigenesis, we tested whether VDR ablation sensitizes the mammary gland to transformation induced by chemical carcinogens or oncogenic overexpression.; Our data indicate that VDR is localized to the ductal epithelial cells and stromal cells in mouse mammary gland and that VDR suppresses ductal elongation and branching morphogenesis during pubertal development. Furthermore, we show that the VDR modulates gene expression during pregnancy, lactation and involution. In the absence of VDR, precocious alveolar development, increased milk release and a delay in mammary gland regression is observed. Cell lines established from mammary tumors which developed in WT and VDR KO mice were utilized to conclusively demonstrate that 1,25D₃ mediated growth arrest and apoptosis in breast cancer cells requires the nuclear VDR. Finally, we found that the VDR allelic content alters the incidence of mammary tumor formation driven by the neu oncogene.; These studies provide the first in vivo evidence that 1,25D₃ and the VDR impact on mammary gland development and suggest that the VDR represents a nutritionally modulated growth regulatory gene within the mammary gland. These data suggest that vitamin D₃ may not only serve as a therapeutic target for early and late stage breast cancers, but may also impact on prevention of breast cancer.