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Carcinogenesis |
in the Epidermis Are Resistant to Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-acetate1
Department of Human Oncology, Medical School, University of Wisconsin, Madison, Wisconsin 53792 [P. J. R., N. E. D., H. A., R. S., J. Z., A. K. V.], and Department of Pathology and Laboratory Medicine, Veterans Administration Hospital and Medical School, University of Wisconsin, Madison, Wisconsin 53792 [T. D. O.]
To determine the role of protein kinase C
in mouse skin carcinogenesis, we have developed transgenic FVB/N mouse lines expressing in the epidermis an epitope-tagged protein kinase C (T7-PKC) regulated by the human keratin 14 promoter. The untreated T7-PKC mice displayed excessive dryness in the skin of the tail with a variable penetrance over time. Histologically, the tail skin showed hyperplasia with evidence of hyperkeratosis. The epidermis of the rest of the T7-PKC mouse was unremarkable. Despite this mild phenotype, the effects of PKC overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7-PKC mice (16 and 37) expressing the T7-PKC transgene were examined for responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA. By immunoblot analysis, the T7-PKC-16 and T7-PKC-37 mice showed an 8- and 2-fold increase of PKC protein. The T7-PKC-16 mice averaged 300% more T7-PKC activity than the T7-PKC-37 mice did. The T7-PKC-37 mice did not manifest any difference in tumor burden or incidence. However, the reduction in papilloma burden at 25 weeks of promotion for the T7-PKC-16 mice relative to wild-type mice averaged 72 and 74% for males and females, respectively. The T7-PKC-16 mice reached 50% papilloma incidence between 12 and 13 weeks of promotion compared with 8 weeks for wild-type mice. Furthermore, the carcinoma incidence was also reduced in T7-PKC-16 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7-PKC-16 females, 37%; wild-type males, 45%; and T7-PKC-16 males, 7%. Thus, PKC when expressed at sufficient levels can suppress skin tumor promotion by TPA.
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