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 zeta- globin promoter which 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. We have demonstrated that the TG.AC mouse line is very sensitive to such known promoters as TPA, benzoyl peroxide, and methylethyl ketone peroxide. Wounding also readily induces papillomas. Our results indicate that expression of the transgene is confined to the skin; for urethan, a potent systemic rodent lung carcinogen, induced only lung tumors in TG.AC mice and at the same incidence as in wildtype nontransgenic FVB mice. Under optimal conditions, a single application of TPA is sufficient to induce one or several papillomas in 10% of treated TG.AC mice. The age of the mice may be an important factor contributing to the relative sensitivity of TG.AC mice to tumor induction. A higher papilloma incidence and shorter latency period appear to be associated with promoter treatment in older mouse groups. Primary keratinocyte cultures from TG.AC mice are being developed in order to study growth regulatory factors that can modify expression of the transgene or for studying chemically induced transformation in vitro. Other studies are being conducted to determine whether the TG.AC model can serve as a short term in vivo model for identifying chemical promoters and/or complete carcinogens that may be hazardous to human health.
