The objective of this project is to develop the TG.AC transgenic mouse line as a model for studying the multistage process of skin carcinogenesis. The TG.AC transgenic mouse line carries a v-Ha-ras oncogene driven by a zetaglobin promoter; the transgene expresses in the skin and confers on the skin the properties of a genetically initiated tissue. The model offers the opportunity to (1) identify chemicals that are promoters or complete carcinogens in the skin; (2) study the molecular mechanisms associated with the induction of papillomas and progression to malignancy; (3) study mechanisms of chemically induced expression or repression of the transgene; and (4) identify the regulatory mechanisms that determine the specificity for transgene expression in the skin and several spontaneous tumor target sites. We have demonstrated that the TG.AC mouse line is sensitive to conventional skin-tumor promoters such as TPA, mezerein and benzoyl peroxide. Environmental agents of concern to human health such as benzene and mirex readily induce papillomas in topically treated TG.AC mice. Papillomas can also be induced in response to wound repair. Full thickness surgical incisions in the dorsal skin induce papillomas in the wound line. The papillomas whether induced by chemical treatment or by incision are at high risk for progressing to malignancy. We have defined and confirmed an age-related response to papilloma induction. This effect is most pronounced under conditions of limited chemical treatment or to a single full-thickness incision. Young mice, 5-10 weeks old, are relatively insensitive, while animals 20 or 30 weeks old exhibit a dramatic increase in papilloma incidence.
