ROLES OF RETINOIDS AND THEIR NUCLEAR RECEPTORS IN THE DEVELOPMENT ANDPREVENTION OF UPPER AERODIGESTIVE TRACT CANCERS

Vitamin A analogs (retinoids) suppress oral and lung carcinogenesis in animal models and prevent the development of second primary tumors in head, neck, and lung cancer patients. These effects result from chang es in the expression of genes that regulate cell growth and differenti ation. Retinoic acid receptors (RARs; -alpha, -beta, and -gamma) and r etinoid X receptors (RXRs; -alpha, -beta, and, -gamma) are retinoid-ac tivated transcription factors, which mediate effects of retinoids on g ene expression. Therefore, alterations in receptor expression or funct ion could interfere with the retinoid signaling pathway and thereby en hance cancer development. We found that the expression of RAR beta was suppressed in more than 50% of oral and lung premalignant lesions in individuals without cancer and in dysplastic lesions adjacent to cance r and in malignant oral and lung carcinomas. The expression of the oth er receptors was not different among normal, dysplastic, and malignant oral tissues. However, the expression of RAR gamma and RXR beta was s omewhat decreased in lung cancers. These results show that RAR beta ex pression is lost at early stages of carcinogenesis in the aerodigestiv e tract and support the hypothesis that the loss of RAR beta expressio n may facilitate the development of some of these cancers.