Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis.
1,25-Dihydroxyvitamin D(3) (1,25D(3)) is the biologically active form of vitamin D(3) that interacts with the nuclear vitamin D(3) 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.
Zinser
Glendon M
GM
Department of Biology, University of Notre Dame, IN 46556, USA.
Sundberg
John P
JP
Welsh
JoEllen
J
D015127:9,10-Dimethyl-1,2-benzanthracene; D000483:Alleles; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002273:Carcinogens; D002455:Cell Division; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000502:physiology*; D012737:Sex Factors; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013997:Time Factors
D002273:Carcinogens; D018167:Receptors, Calcitriol; D015127:9,10-Dimethyl-1,2-benzanthracene; D001973:Bromodeoxyuridine