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A transgenic mouse model (TG.AC) for skin carcinogenesis: inducible transgene expression as a second critical event.

The v-Ha-ras transgenic TG.AC mouse line behaves as a genetically initiated model for mouse skin tumorigenesis with enhanced susceptibility to skin carcinogens. TG.AC mice develop epidermal papillomas in fewer than 20 weeks in response to the topical application of a variety of chemicals such as complete carcinogens, phorbol ester-type tumor promoters, and nonphorbol ester-type tumor promoters as well as to full-thickness skin wounds or plucking of the dorsal hair. We have found that the pedunculated epidermal papillomas can arise as focal hyperplasias from the permanent portion of the follicular epithelium. Expression of the v-Ha-ras transgene serves as a marker for tumor development since it is expressed at significant levels in the papilloma precursors, focal follicular hyperplasias, and the papillomas but not in the surrounding skin. Transgene expression colocalizes with increased cell proliferation in the papillomas as compared to non-tumor bearing surrounding skin. Malignant skin tumors, primarily squamous cell carcinomas and sarcomas, develop from sites of papilloma development in approximately 40% of papilloma bearing mice. As well as significant levels of transgenic v-Ha-ras expression, some of the malignancies also exhibit karyotypic changes which include trisomy of chromosome six or fifteen, but not chromosome seven. We believe that the TG.AC mouse line serves not only as a model for studying the mechanisms of skin tumorigenesis, but will also be a useful adjunct to the two year NTP toxicity/carcinogenicity studies by identifying carcinogens in fewer than 20 weeks.