Over-expression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor null mice

The vitamin D receptor (VDR) ligand, 1,25(OH)(2)D(3), reduces proliferation and enhances differentiation and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR 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 over-expression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR null animals over-express elements of the Hh pathway [Sonic Hedgehog (Shh, 2.02 fold), Patched1 1.58 fold, Smoothened 3.54 fold, Gli1 1.17 fold, and Gli2 1.66 fold]. This over-expression occurs at an age (11 weeks) where epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA or UVB induced tumors in the VDR null mice also over-express elements of this pathway. Moreover, 1,25(OH)(2)D(3) down-regulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms.