Genetic deletion of p21(WAF1) enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis

Tumor suppression by p53 is believed to reside in its ability to regulate g ene transcription, including up-regulation of p21(WAF1). In p53(-/-) mice, chemical- or oncogene-induced skin tumors undergo accelerated malignant con version, To determine the contribution of the p21(WAF1) gene product to epi dermal carcinogenesis, animals +/+, +/-, and -/- for a null mutation in the p21(WAF1) gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthrace ne, followed by 5 mu g of TPA two times/week for 20 weeks. Papilloma freque ncy was higher in the p21(WAF1)-deficient mice. However, the frequency of m alignant conversion was similar among all three genotypes, After TPA treatm ent, all genotypes developed epidermal hyperplasia, although the labeling i ndex was lower in p21(WAF1) (-/-) epidermis compared with p21(WAF1) (+/+), Furthermore, the expression of differentiation markers was the same across genotypes in untreated or TPA-treated epidermis, Similar frequencies of mal ignant conversion were also observed in an in vitro assay. Thus, p21(WAT1) suppresses early stages of papilloma formation but not malignant progressio n in mouse skin carcinogenesis, and decreased levels of p21(WAF1) do not ac count for the enhanced malignant conversion of p53 null epidermal tumors.