ANDROGENS REGULATE PROLIFERATION OF HUMAN PROSTATE-CANCER CELLS IN CULTURE BY INCREASING TRANSFORMING GROWTH-FACTOR-ALPHA (TGF-ALPHA) AND EPIDERMAL GROWTH-FACTOR (EGF) TGF-ALPHA RECEPTOR/

Androgens affect growth of the prostate gland and many prostate cancer s. Androgens could mediate their mitogenic effects on prostate cells b y an autocrine loop involving epidermal growth factor (EGF) and transf orming growth factor (TGF)-alpha that bind to the EGF/TGF-alpha recept or. We examined the effects of 5 alpha-dihydrotestosterone (DHT) and t estosterone (T), EGF, and EGF-alpha on cell proliferation and H-3-thym idine incorporation in an androgen-dependent human prostate cancer cel l line, ALVA101, in serum-free medium. The regulation of TGF-alpha and EGF/TGF-alpha receptor messenger RNA (mRNA) levels were determined by Northern blot analysis and EGF/TGF-alpha receptor protein by immunobl ot. After 24 h of treatment of ALVA101 cells with DHT (10(-8) M) or T (10(-8) M), TGF-alpha mRNA levels increased 3- and 2.5-fold, respectiv ely, and EGF/TGF-alpha receptor mRNA levels 2- and 1.5-fold, respectiv ely. Cell numbers increased at day 5 in response to 10(-8) M DHT (18%, P < 0.01), 10(-8) M T (15%, P < 0.01), 20 ng/ml EGF (16%, P < 0.01), and 50 ng/mL TGF-alpha (34%, P < 0.01). DHT combined with TGF-alpha or T combined with EGF increased cell number 43% and 40% above control, respectively (P < 0.01 vs. DHT, P < 0.05 vs. TGF-alpha, T, EGF alone). The anti-EGF/TGF-alpha receptor antibody (528) blocked the cell proli feration induced by either DHT or TGF-alpha. We conclude that DHT and T stimulate synthesis of TGF-alpha and EGF/TGF-alpha receptor mRNAs an d EGF/TGF-alpha receptor content in ALVA101 cells. This mitogenic effe ct of androgen on ALVA101 cells may involve TGF-alpha and the EGF/TGF- alpha receptor autocrine loop.