TGFa is Dispensable for Skin Tumorigenesis in Tg.AC Mice*

Alterations in growth factor signaling pathways frequently accompany the development and maintenance of epithelial neoplasia. Transforming growth factor a (TGFa) and its epidermal growth factor receptor have been thought to play an especially important role in epithelial neoplasia. In this study, mice were derived genetically deficient (null) in functional TGFa expression and carrying the Tg.AC/v-Ha-rus transgene. The goals were to determine if (a) papillomagenesis was dependent on TGFa and (b) progression to malignancy was dependent on TGFa expression. Groups of male and female mice heterozygous or homozygous for the TGFa null allele and hemizygous for the Tg.AC transgene were treated twice weekly for 10 or 15 wk with doses of 12-0-tetradecanoylphorbol-13-acetate (TPA) known to produce papillomas in Tg.AC mice. Papillomas were readily induced in both male and female TGFa null mice. Malignant progression of papillomas was observed in all TGFa null treatment groups. Additionally. we examined the response of TGFa null mice to full thickness dorsal wounds, a stimulus known to promote papillomagenesis in Tg.AC mice. As in the TPA study, papillomas were induced in both male and female TGFa null mice. These studies indicate that TGFa is not required for the induction and maintenance of papillomas nor is it essential for the malignant conversion of papillomas in T g A C mice. Keywords. Transgenic mice; v-Ha-rus; TPA; wounding; epidermal growth factor receptor (EGFR); oncogen