Genetic Deletion of p21 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 gene transcription, including up-regulation of p21. In p53(2/2) mice, chemicalor oncogene-induced skin tumors undergo accelerated malignant conversion. To determine the contribution of the p21 gene product to epidermal carcinogenesis, animals 1/1, 1/2, and 2/2 for a null mutation in the p21 gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthracene, followed by 5 mg of TPA two times/week for 20 weeks. Papilloma frequency was higher in the p21-deficient mice. However, the frequency of malignant conversion was similar among all three genotypes. After TPA treatment, all genotypes developed epidermal hyperplasia, although the labeling index was lower in p21 (2/2) epidermis compared with p21 (1/1). Furthermore, the expression of differentiation markers was the same across genotypes in untreated or TPA-treated epidermis. Similar frequencies of malignant conversion were also observed in an in vitro assay. Thus, p21 suppresses early stages of papilloma formation but not malignant progression in mouse skin carcinogenesis, and decreased levels of p21 do not account for the enhanced malignant conversion of p53 null epidermal tumors.