Tumor promoter 12-O-tetradecanoylphorbol 13-acetate, like epidermal growth factor, stimulates cell proliferation and inhibits differentiation of mouse mammary epithelial cells in culture.

12-O-Tetradecanoylphorbol 13-acetate (TPA) is a potent tumor promoter and shares several biological activities of epidermal growth factor (EGF). Recently we have shown that EGF stimulates DNA synthesis and inhibits milk protein synthesis induced by insulin, cortisol, and prolactin in a primary mouse mammary epithelial cell culture [Taketani, Y. & Oka, T. (1983) FEBS Lett., in press]. Using this system, we examined the biological action of TPA in reference to that of EGF. TPA stimulated cell proliferation and inhibited the synthesis of milk proteins casein and alpha-lactalbumin during a 5-day culture. The ED50 was about 2.5 ng/ml for DNA synthesis and 0.1 ng/ml for milk protein synthesis. Removal of TPA from the medium normalized DNA synthesis completely and casein synthesis partially. The ability of various TPA analogs to stimulate DNA synthesis and inhibit casein synthesis correlated with their potency as tumor promoters. Both TPA and EGF decreased the specific prolactin binding of cultured cells by approximately equal to 50%. These results indicate that TPA, like EGF, switches the developmental course of mammary epithelium from differentiation to proliferation.