Keratin Modifications in Epidermis, Papillomas, and Carcinomas during Two-Stage Carcinogenesis in the SENCAR Mouse1

To elucidate the role of keratin modification in tumor pro motion, we investigated the keratin polypeptide patterns of mouse epidermis, papillomas, and carcinomas throughout an initiation-promotion experiment. The epidermal keratin modifi cations induced by repetitive 12-O-tetradecanoylphorbol-13acetate treatments in both initiated and noninitiated mouse skin were essentially identical to those observed with a single 12-O-tetradecanoylphorbol-13-acetate application. These changes were even more pronounced in epidermal papillomas. In addition, the keratins of the papillomas displayed greater charge heterogeneity, particularly among the high-molecularweight keratins (M, 60,000 to 62,000). As the experiment progressed, there appeared to be a selective loss of one group of high-molecular-weight keratins (M, 62,000) in some of the papillomas. Interestingly, the carcinomas that appeared at this time had significant reduction in both groups of high-molecularweight keratins. In fact, the keratin profiles of carcinomas were very similar to the patterns observed in basal cells after a single 12-O-tetradecanoylphorbol-13-acetate treatment of adult epi dermis. This may indicate that the program of keratin expres sion of a carcinoma becomes permanently fixed at a basal cell pattern. Changes in keratin patterns may serve as a biochem ical marker of malignant progression in mouse epidermis.