12-O-TETRADECANOYLPHORBOL-13-ACETATE PROMOTION OF TRANSGENIC MICE EXPRESSING EPIDERMAL-TARGETED V-FOS INDUCES RAS(HA)-ACTIVATED PAPILLOMAS AND CARCINOMAS WITHOUT P53 MUTATION - ASSOCIATION OF V-FOS EXPRESSION WITH PROMOTION AND TUMOR AUTONOMY

Transgenic mice that expressed v-fos exclusively in the epidermis by m eans of a human keratin K1-based targeting vector (HK1.fos) developed preneoplastic epidermal hyperplasia and hyperkeratosis after long late ncy and an associated wound promotion stimulus. To assess the requirem ents for papilloma formation and malignant conversion and determine th e sensitivity to a chemical promotion stimulus, HK1.fos mice were prom oted with 12-O-tetradecanoylphorbol-13-acetate (TPA). HK1.fos mice wer e sensitive to TPA promotion but developed papillomas only after long latency (20-30 weeks of promotion) and in relatively few numbers per a nimal, suggesting the necessity of an additional genetic event prior t o overt lesion formation. Consistent with this idea, at 60 weeks, on c essation of TPA promotion, these HK1.fos TPA-papillomas were found to be autonomous, TPA-independent tumors which persisted, grew larger, an d converted to malignancy. Analysis of HK1.fos tumor RNA and DNA ident ified endogenous c-ras(Ha) mutations at codons 12 and 61 in papillomas and carcinomas; however, no p53 tumor suppressor gene mutations were detected. These data indicate that epidermal expression of v-fos induc es sensitivity to TPA promotion, but since additional genetic events, such as endogenous c-ras(Ha) activation, appear to be required in tumo rigenesis, v-fos may predominantly play a role in the mechanism of pro motion to achieve papilloma autonomy and TPA independence. Furthermore , spontaneous malignant conversion in this model does not appear to in volve mutations in the p53 tumor suppressor gene.