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Genetic Deletion of p21^WAF1 Enhances Papilloma Formation but not Malignant Conversion in Experimental Mouse Skin Carcinogenesis

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research [W. C. W., A. S.], Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute [D. L. M., E. F-S., H. H., S. H. Y.], and Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Disorders [C. D.], NIH, Bethesda, Maryland 20892, and ROW Sciences, Inc., Rockville, Maryland 20878 [E. S., E. M.]

Tumor suppression by p53 is believed to reside in its ability to regulate gene transcription, including up-regulation of p21^WAF1. In p53(-/-) mice, chemical- or oncogene-induced skin tumors undergo accelerated malignant conversion. To determine the contribution of the p21^WAF1 gene product to epidermal carcinogenesis, animals +/+, + /-, and -/- for a null mutation in the p21^WAF1 gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthracene, followed by 5 µg of TPA two times/week for 20 weeks. Papilloma frequency was higher in the p21^WAF1-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^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 malignant conversion were also observed in an in vitro assay. Thus, p21^WAF1 suppresses early stages of papilloma formation but not malignant progression in mouse skin carcinogenesis, and decreased levels of p21^WAF1 do not account for the enhanced malignant conversion of p53 null epidermal tumors.

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