Analysis of the Ability of 12-O-Tetradecanoylphorbol-13-Acetate to Induce Epidermal Hyperplasia, Transforming Growth Factor-α, and Skin Tumor Promotion in wa-1 Mice

Wa-1 mutant mice possess a defect in the production of transforming growth factor-α (TGF-α) that leads to a phenotype characterized by wavy hair and curly whiskers. In light of recent evidence indicating the importance of TGF-α in epithelial tumorigenesis, this study characterizes the responsiveness of wa-i mice to skin tumor promotion by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). The responsiveness of wa-1 mice to TPA was compared with that of SENCAR and C57BL/6 mice, representing mouse lines highly sensitive and resistant to skin tumor promotion, respectively. Wa-1 mice were found to be very resistant to skin tumor promotion by TPA after initiation with 10nmol DMBA, similar to C57BL/6 mice. TPA failed to induce a dramatic increase in TGF-α mRNA and protein in the skin of wa-I mice, whereas TGF-α mRNA and protein were dramatically induced in the skin (both epidermis and dermis) of SENCAR and C578L/6 mice. TPA treatment dramatically increased mRNA levels of two other EGF receptor ligands, amphiregulin and heparin binding-EGF, however, in the skin of all three mouse lines. Comparison of histologic changes in skin revealed that wa-1mice exhibited only modest sustained epidermal hyperplasia after multiple treatments with TPA, similar in magnitude to that of C57BL/6 mice and significantly lower than that of SENCAR mice. The current data indicate that wa-1 mice are relatively resistant to TPA promotion. Possible mechanisms for this resistance are discussed