Inactivation of the Vitamin D Receptor Enhances Susceptibility of Murine Skin to UV-Induced Tumorigenesis

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) is the biologically active ligand for the vitamin D receptor (VDR). VDR^−/− mice have a hair follicle-cycling defect resulting in alopecia. However, mice lacking 25-hydroxyvitamin D₃ 1α-hydroxylase (CYP27B1^−/−), and having no circulating 1,25(OH)₂D₃, have normal follicular function. These mouse models indicate that VDR functions independently of 1,25(OH)₂D₃ in regulating hair-follicle cycling. Here, we show that VDR^−/− mice rapidly develop chemically induced skin tumors, whereas CYP27B1^−/− and wild-type mice do not, indicating that VDR, and not the 1,25(OH)₂D₃ ligand, is essential for protection against skin tumorigenesis. Because the majority of human skin cancer results from exposure to UV, the susceptibility of VDR^−/− mice to this carcinogen was also evaluated. VDR^−/− mice developed UV-induced tumors more rapidly and with greater penetrance than did VDR^+/+ mice. p53 protein levels were upregulated at similar rates in UV-treated keratinocytes of VDR^−/− and VDR^+/+ mice. However, rates of thymine-dimer repair and UV-induced apoptosis were significantly lower in VDR^−/− epidermis compared with the wild type epidermis. UV-induced epidermal thickening was also attenuated in VDR^−/− skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes and adaptation of the skin to chronic UV exposure.