MOUSE SKIN TUMOR PROGRESSION RESULTS IN DIFFERENTIAL EXPRESSION OF RETINOIC ACID AND RETINOID-X RECEPTORS

Retinoids are powerful regulators of epidermal cell growth and differe ntiation and are widely used in the prevention and treatment of skin d isorders and cancers in humans. Since many of the effects of retinoids on cell growth and differentiation are mediated by nuclear retinoid r eceptors (RARs and RXRs), we were interested in determining RAR and RX R gene expression during mouse skin tumor progression. The two-stage s ystem of mouse skin carcinogenesis was used to generate papillomas and carcinomas, and the different stages of malignant progression (papill omas, differentiated squamous cell carcinomas, undifferentiated squamo us cell: carcinomas, and spindle cell carcinomas) were characterized i n each tumor by specific keratin expression prior to receptor characte rization. Using in situ hybridization analysis, we show that the two m ajor RAR isoforms (alpha 1 and gamma 1), which account for most of RAR s in the skin, were expressed in both the basal and suprabasal layers in mouse epidermis. In contrast, RXR alpha transcripts were compartmen talized to the basal cell layers and concentrated in hair follicles. D uring skin tumor progression, RAR (alpha 1 and gamma 1) transcripts we re down-modulated in malignant tumor cells, whereas RXR (alpha and bet a) transcript expression was expanded in papillomas and carcinomas as the number of undifferentiated cells also increased. RXR gamma was not detected in the skin or at any stage during skin tumor progression. S pindle cell tumors lacked markers of the keratinocyte phenotype and lo st RAR expression, yet retained expression of RXR alpha and beta. The increased abundance of transcripts for RXRs and decreased presence of RARs in skin. tumor progression may favor other nuclear signal transdu ction pathways requiring RXR for heterodimer formation and contribute to phenotypic progression of cancer cells.