Overexpression of Hedgehog Signaling Is Associated with Epidermal Tumor Formation in Vitamin D Receptor–Null Mice

Thevitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for theVDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of theVDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17-fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in theVDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)2D3 downregulates the expression of some members of theHh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)2D3. Our results suggest that increased expression of Shh in the keratinocytes of theVDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms.