Malignant transformation of DMBA/TPA-induced papillomas and Nevi in the skin of mice selectively lacking retinoid-X-receptor α in epidermal keratinocytes

Retinoid-X-receptor alpha (RXR alpha), a member of the nuclear receptor (NR) superfamily, is a ligand-dependent transcriptional regulatory factor. It plays a crucial role in NR signalling through heterodimerization with some 15 NRs. We investigated the role of RXR alpha and its partners on mouse skin tumor formation and malignant progression upon topical DMBA/TPA treatment. In mutants selectively ablated for RXR alpha in keratinocytes, epidermal tumors increased in size and number, and frequently progressed to carcinomas. As keratinocyte-selective peroxisome proliferator-activated receptor gamma ( PPAR gamma) ablation had similar effects, RXR alpha/PPAR gamma heterodimers most probably mediate epidermal tumor suppression. Keratinocyte-selective RXR alpha-null and vitamin-D-receptor null mice also exhibited more numerous dermal melanocytic growths (nevi) than control mice, but only nevi from RXR alpha mutant mice progressed to invasive human-melanoma-like tumors. Distinct RXR alpha-mediated molecular events appear therefore to be involved, in keratinocytes, in cell-autonomous suppression of epidermal tumorigenesis and malignant progression, and in non-cell-autonomous suppression of nevi formation and progression. Our study emphasizes the crucial role of keratinocytes in chemically induced epidermal and melanocytic tumorigenesis, and raises the possibility that they could play a similar role in UV-induced tumorigenesis, notably in nevi formation and progression to melanoma.