EXPRESSION OF A P53 MUTANT IN THE EPIDERMIS OF TRANSGENIC MICE ACCELERATES CHEMICAL CARCINOGENESIS

To develop an in vivo model for studying the role of the p53 tumor sup pressor in skin carcinogenesis, a murine p53(172H) mutant (equivalent to human p53(175H)) was expressed in the epidermis of transgenic mice, utilizing a targeting vector based on the human keratin 1 gene (HK1.p 53(m)), HK1.p53(m) mice developed normally and did not exhibit an obvi ous epidermal phenotype or develop spontaneous tumors. However, these mice demonstrated an increased susceptibility to a two-stage chemical carcinogenesis protocol, with the rate of formation and number of papi llomas being dramatically increased as compared to non-transgenic cont rols, The majority of papillomas in control mice regressed after termi nation of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, wherea s p53(m) papillomas progressed to carcinomas and metastases. In additi on, more advanced malignancy, i.e., undifferentiated spindle cell carc inomas, were exclusively observed in p53(m) mice. Increased bromodeoxy uridine (BrdU) labeling, accompanied by decreased expression of p21, w as observed in HK1.p53(m) papillomas. In situ examination of centrosom es in HK1.p53(m) papillomas also revealed marked abnormalities, with 7 5% of the cells containing greater than or equal to 3 centrosomes/cell , whereas centrosome numbers in papillomas from control animals remain ed normal. These data suggest that the accelerated tumorigenesis obser ved in chemically-treated p53(m) mice is most likely due to increased genomic instability resulting from an inhibition of G1 arrest and abno rmal amplification of centrosomes.