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1 Department of Radiation Oncology, Arizona Cancer Center and 2 Department of Epidemiology and Biostatistics, College of Public Health, The University of Arizona, Tucson, AZ; and
3 Basic Research Laboratory, National Cancer Institute, Frederick, MD
Requests for reprints: G. Tim Bowden, Arizona Cancer Center, Room 4999, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: (520) 626-6006; Fax: (520) 626-4979. E-mail: tbowden{at}azcc.arizona.edu
UVB radiation is a complete carcinogen able to initiate, promote, and progress keratinocyte cells toward carcinogenesis. Exposure to UVB leads to the propagation of a number of signal transduction pathways resulting in increased DNA binding of transcription factors, including activator protein-1 (AP-1), and subsequent gene expression. To test the hypothesis that AP-1 activation plays a role in the promotion of UVB-induced skin tumors, a dominant negative c-jun (TAM67) mutant transgene was expressed in the epidermis of SKH-1 hairless mice and bred with mice expressing an AP-1 luciferase reporter gene. Single UVB exposure experiments showed a significant decrease in AP-1 activity, as measured by luciferase levels, in mice expressing TAM67 72 h postexposure. Transgenic and nontransgenic littermates were placed into a chronic UVB exposure experiment, three exposures per week for 25 weeks. Expression of TAM67 reduced the number of tumors per mouse by 58% and tumor sizes were 79% smaller than the tumors present in the nontransgenic study group. These tumors were histologically identified as squamous cell carcinomas. TAM67 had no effect on UVB-induced hyperplasia because comparable epidermal thickening was observed in both study groups over a 5-day period post-UVB exposure. Immunohistochemical analysis showed a reduction in the number of cyclin D1-expressing cells in squamous cell carcinoma samples removed from the TAM67 study group. These data show that TAM67 can inhibit UVB-induced squamous cell carcinoma formation, suggesting that AP-1 is a good candidate target for the development of new chemoprevention strategies to prevent sunlight-induced skin cancers.
Key Words: UVB • activator protein-1 • TAM67 • skin carcinogenesis • SKH-1 hairless mice
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