Vitamin D3 receptor ablation sensitizes skin to chemically induced tumorigenesis

1,25-Dihydroxyvitamin D-3 (1,25D(3)) is the biologically active form of vitamin D3 that interacts with the nuclear vitamin D3 receptor (VDR) to modulate gene expression in a tissue-specific fashion. 1,25D(3) is a potent regulator of cell proliferation, differentiation and apoptosis in a variety of cell types, including keratinocytes. In these studies, we assessed the sensitivity of mice homozygous for a null allele of the VDR (VDR-/- mice) and their wild-type counterparts (VDR+/+ mice) to oral administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA). Although the protocol was optimized for the induction of mammary tumors, 85% of VDR-/- mice developed persistent skin tumors within 60 days of carcinogen exposure. In VDR-/- mice exposed to DMBA, papillomas arose on all areas of the body, with an average tumor burden of 5.3 papillomas/mouse. No papillomas or any other skin lesions were observed in age- and sex-matched VDR+/+ mice dosed with DMBA and followed for 6 months. The majority (80%) of skin tumors that developed in VDR-/- mice were classified histologically as sebaceous, squamous or follicular papillomas. Other types of lesions, including basal cell carcinoma, hemangioma and melanotic foci, were occasionally observed in VDR-/- mice (but not in VDR+/+ mice) exposed to DMBA. Quantification of epidermal thickness and BrdU incorporation indicated that skin from VDR-/- mice exhibited hyperproliferation beginning at 7 weeks of age, which was exacerbated by DMBA treatment. Untreated aging VDR-/- mice did not exhibit tumor formation, but did develop a progressive skin phenotype characterized by thickened wrinkled skin, dermoid cysts and long curly nails. Together with previous reports that 1,25D(3) inhibits papilloma formation induced by topical DMBA-TPA regimens, our observation of enhanced sensitivity of VDR-/- mice to chemically induced skin carcinogenesis offers compelling evidence that disruption of VDR signaling predisposes to neoplasia.