1. ¹Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
2. ²Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA

Correspondence: Dr Paul N. MacDonald, Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44116, USA. E-mail: pnm2@case.edu

Received 15 October 2007; Revised 24 March 2008; Accepted 27 March 2008; Published online 29 May 2008.

Abstract

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 1-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.