Tumor suppression by p27(Kip1) and p21(Cip1) during chemically induced skin carcinogenesis

p27(Kip1)and p21(Cip1) are cyclin dependent kinase inhibitors which can arr est cell proliferation and p27 is a tumor suppressor gene. To address the m echanism of tumor suppression by p27 and to determine if p21 has a tumor su ppressor phenotype, we utilized the two stage skin carcinogenesis model on p27 and p21 knockout mice. In this model, initiation, which involves mutati on of H-ras induced by DMBA, can be distinguished from promotion induced by TPA, and progression to carcinoma. The mean number of papillomas did not d iffer between p27 - / - and control littermates, but papilloma growth rate was increased and carcinomas developed earlier. Thus, p27 deficiency did no t enhance initiation, but resulted in more rapid clonal expansion of initia ted cells during promotion. TPA treatment reduced p27 expression in keratin ocytes also supporting a role for p27 during promotion. Tumors from p27 - / - mice contained mutant H-ras indicating that p27 deficiency did not subst itute for mutant ras and further, that during ras driven tumor growth, p27 is partially antagonistic since its removal led to faster growth. The treat ed p27 - / - mice also developed intestinal adenomas, p21 - / - mice did no t display a significant increase in tumor numbers, growth rate or progressi on to carcinomas and these tumors also had mutated H-rns. Carcinomas from p 21 - / - mice were more poorly differentiated with a high frequency of anap lastic spindle cell carcinomas. Thus p21 deficiency mainly resulted in high er grade undifferentiated tumors.