||Androgens affect growth and functional integrity of the prostate gland, and many prostate cancers retain dependency on androgens for growth. The transforming growth factor (TGF)-ce binds to the epidermal growth factor (EGF) receptor and is an autocrine growth factor, which could mediate the mitogenic effect of steroid hormones. To test this hypothesis, we examined the effects of 5a-dihydrotestosterone (DHT) and testosterone on cell proliferation, regulation of TGF-a and EGF receptor mRNA levels and EGF receptor content in an androgen-sensitive human prostate cancer cell line (ALVA 101). ALVA 101 cells cultured in serum-free medium without androgen expressed a TGF-a mRNA transcript of 4.8 kb and an EGF receptor mRNA transcript of 10 kb. After 24 h treatment with DHT (108M) or testosterone (10~8M), TGF-a mRNA levels increased 3-and 2.5-fold, respectively, and EGF receptor mRNA levels 2- and 1.5-fold, respectively. The mitogenic effects of androgens and EGF or TGF-a on the proliferation of ALVA 101 cells were then examined. In serum-free medium, cell numbers increased at day 5 in response to 10-8M DHT (18%, p<0.01), 10-8M testosterone (15%, p<0.01), 20 ng/ml EGF (16%, p<0.01) and 50 ng/ml TGF-a (34%, p<0.01). In addition, DHT combined with TGF-a or testosterone combined with EGF increased cell number 43% and 40% above control, respectively. (p<0.01 vs. DHT, p<0.05 vs. TGF-a, testosterone or EGF alone). Further, 3H-thymidine incorporation studies confirmed the mitogenic effects of androgens and TGF-a or EGF on ALVAlOl cells. The anti-EGF receptor antibody (528) blocked the cell proliferation induced by either DHT or TGF-a. We conclude that DHT and testosterone stimulate synthesis of TGF-a and EGF receptor mRNAs and EGF receptor content in ALVAlOl cells, and that DHT and testosterone may enhance ALVAlOl cell proliferation through an autocrine mechanism involving TGF-a and the EGF/TGF-a receptor.""