1. ¹Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104; INSERM U596; ULP, Collège de France) and Institut Clinique de la Souris, B.P.10142, 67404, ILLKIRCH, Strasbourg, France
2. ²College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA
3. ³Departamento de Genética y Biología Molecular CINVESTAV-IPN, Mexico
4. ⁴Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
5. ⁵Unité CIG Science, Centre Intégratif de Génomique (CIG) UNIL, Lausanne, Switzerland

Correspondence: Arup Kumar Indra, Department of Pharmaceutical Sciences, OSU, Corvallis, Oregon 97331, USA. E-mail: arup.indra@oregonstate.edu; Pierre Chambon, IGBMC, BP 163 67404 Illkirch Cedex, France. E-mail: chambon@igbmc.u-strasbg.fr

⁶Present address: Department of Pharmaceutical Sciences, Program in Molecular and Cellular Biology, Oregon State University, Corvallis, Oregon 97331, USA.

⁷These authors contributed equally to this work

Received 2 June 2006; Revised 6 October 2006; Accepted 10 October 2006; Published online 15 February 2007.

Abstract

Retinoid-X-receptor (RXR), 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 and its partners on mouse skin tumor formation and malignant progression upon topical DMBA/TPA treatment. In mutants selectively ablated for RXR in keratinocytes, epidermal tumors increased in size and number, and frequently progressed to carcinomas. As keratinocyte-selective peroxisome proliferator-activated receptor gamma (PPAR) ablation had similar effects, RXR/PPAR heterodimers most probably mediate epidermal tumor suppression. Keratinocyte-selective RXR-null and vitamin-D-receptor null mice also exhibited more numerous dermal melanocytic growths (nevi) than control mice, but only nevi from RXR mutant mice progressed to invasive human-melanoma-like tumors. Distinct RXR-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.