Ultraviolet Radiation Induction of Squamous Cell Carcinomas in p53 Transgenic Mice1

Mutations of the p53 gene have been implicated in the pathogenesis of cutaneous squamous cell carcinoma (SCC). To examine the role ol'/o.f in skin carcinogenesis, we observed the development of skin cancers in p53 transgenic mice which carry multiple copies of a mutant alÃ-eleof the p53 gene with or without chronic UVB radiation. Thirty-one tumors developed in 19 UV-irradiated p53 transgenic mice versus 14 of 19 in the control group; 9 p53 transgenic mice but none of the control mice developed multiple tumors. Histologically, 14 of 14 tumors in the CD-I mice were SCCs. In the p53 transgenic mice, 25 of 31 tumors were SCCs, and 6 were benign tumors. The mean time to appearance of tumors did not differ between CD-I mice (26.3 weeks) and the p53 transgenic mice (25.7 weeks; P = 0.512). The p53 protein, which was undetectable by immunohistochemistry in the keratinocytes of CD-I mice, was elevated in 93% (13 of 14) of tumors from CD-I mice. These data indicate that mutation of the p53 gene is an important step in the development of SCC. p53 mutations do not alter the latent period of UV-induced SCC but significant!) in crease the number of tumors and the propensity for multiple tumor development. Several lines of evidence suggest that mutation of the p53 tumor suppressor gene is involved in the development of SCC. Mutations of the p53 gene have been observed in UV-induced SCC in humans (3) and animals (13). Most of the mutations occurred at dipyrimidine sequences, with C^>T or CC-»TT transitions predominating, sug gesting that these mutations are direct results of UV radiation (3). Other workers have demonstrated that the amount of p53 protein is elevated in SCC compared to normal epithelial cells (14). Altered expression of the p53 gene was also found during murine epithelial cell transformation (15). To study the role of p53 gene mutation in the development of SCC, we have used a p53 transgenic mouse model (16) in skin photocarcinogenesis experiments. The p53 transgenic mice, which was gener ated by introducing mutant p53 gene fragments from a tumor cell line into fertilized eggs, carry 10-20 copies of the mutant p53 gene. Our results indicate that the p53 transgenic mice have a higher incidence of SCC and are prone to multiple tumors, but the latent period for the development of SCC is similar to control mice.