EPIDERMAL GROWTH-FACTOR RECEPTOR-DEPENDENT STIMULATION OF AMPHIREGULIN EXPRESSION IN ANDROGEN-STIMULATED HUMAN PROSTATE-CANCER CELLS

Amphiregulin is a heparin-binding epidermal growth factor (EGF)-relate d peptide that binds to the EGF receptor (EGF-R) with high affinity. I n this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhan ce EGF-R expression in the androgen-sensitive LNCaP human prostate car cinoma cell line, and it has been suggested that androgenic stimuli ma y regulate proliferation, in part, through autocrine mechanisms involv ing the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimu lation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parall el studies using the estrogen-responsive breast carcinoma cell line, M CF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting tha t amphiregulin can mediate androgen-stimulated LNCaP proliferation. To gether, these results implicate an androgen-regulated autocrine loop c omposed of amphiregulin and its receptor in prostate cancer cell growt h and suggest that the mechanism of steroid hormone regulation of amph iregulin synthesis may occur through androgen upregulation of the EGF- R and subsequent receptor-dependent pathways.