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Loss of Retinoic Acid Receptors in Mouse Skin and Skin Tumors Is Associated with Activation of the ras^Ha Oncogene and High Risk for Premalignant Progression

Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Basic Science, National Cancer Institute, NIH, Bethesda, Maryland 20892 [N. D., G. S., C. J., S. R., E. G., T. T., L. M. D. L., S. H. Y.], and Molecular Medicine Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104-2092 [S. J. C.]

Retinoic acid receptor transcripts (RAR and RAR) are decreased in benign mouse epidermal tumors relative to normal skin and are almost absent in carcinomas. In this report, the expression of RAR and RAR proteins was analyzed by immunoblotting in benign skin tumors induced by two different promotion protocols designed to yield tumors at low or high risk for malignant conversion. RAR was slightly reduced in papillomas promoted with 12-O-tetradecanoylphorbol-13-acetate (low risk) and markedly decreased or absent in papillomas promoted by mezerein (high risk). However, mezerein also caused substantial reduction of RAR in nontumorous skin. RAR was not detected in tumors from either protocol and was greatly reduced in skin treated by either promoter. Both RAR and RAR proteins were decreased in keratinocytes overexpressing an oncogenic v-ras^Ha gene, and RAR was underexpressed in a benign keratinocyte cell line carrying a mutated c-ras^Ha gene. Introduction of a recombinant RAR expression vector into benign keratinocyte tumor cells reduced the S-phase population and inhibited [³H]thymidine incorporation in response to retinoic acid. Furthermore, transactivation of B-RARE-tk-LUC by retinoic acid was markedly decreased in keratinocytes transduced with the v-ras^Ha oncogene (v-ras^Ha-keratinocytes). Blocking protein kinase C function in v-ras^Ha-keratinocytes with bryostatin restored RAR protein to near normal levels, reflecting the involvement of protein kinase C in RAR regulation. Both RAR and RAR are down-regulated in cultured keratinocytes by 12-O-tetradecanoylphorbol-13-acetate, further implicating PKC in the regulation of retinoid receptors. Our data suggest that modulation of RARs could contribute to the neoplastic phenotype in mouse skin carcinogenesis and may be involved in the differential promoting activity of mezerein and 12-O-tetradecanoylphorbol-13-acetate, particularly for selecting tumors at high risk for malignant conversion.

¹ To whom requests for reprints should be addressed, at National Cancer Institute. Building 37, Room 3B25, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-2162; Fax: (301) 496-8709; E-mail: yuspas@dc37a.nci.nih.gov.

Received 6/ 3/96. Accepted 9/ 4/96.

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