Amphiregulin is coordinately expressed with heparin-binding epidermal growth factor-like growth factor in the interstitial smooth muscle of the humanprostate

Peptide growth factors have been proposed as mediators of smooth muscle-epi thelial cell interactions in the human prostate; however, the identity of t hese molecules has not been established. In this study, we compared express ion levels of messenger RNAs (mRNAs) encoding the epidermal growth factor ( EGF) receptor-related receptor tyrosine kinases (ErbB1 through 4), the six EGF receptor ligands, EGF, transforming growth factor (TGF)-alpha, amphireg ulin (ARG), HB-EGF, betacellulin, and epiregulin, and the related molecule heregulin-alpha, in a series of 10 prostate tissue specimens. Only EGF show ed a disease-specific association, with increased mRNA levels in four of fi ve PCa specimens in comparison to matched normal tissue from the same subje ct. In contrast, ARG and HB-EGF mRNAs showed a coordinate pattern of expres sion in 7/10 specimens that was distinct from all other growth factor or re ceptor genes examined and from mRNAs for prostate specific antigen, the and rogen receptor and GAPDH, a housekeeping enzyme. Analysis of an additional series of benign prostatic hyperplasia and prostate cancer specimens from 6 0 individuals confirmed that ARG and HB-EGF mRNA levels varied in a highly coordinate manner (r = 0.93; P < 0.0001) but showed no association with dis ease. ARG was immunolocalized largely to interstitial smooth muscle cells ( SMC), previously identified as the site of synthesis of IIB-EGF in the pros tate, while the cognate ARG and HB-EGF receptor, ErbB1, was localized exclu sively to ductal epithelial cells and carcinoma cells. Although ARG was a r elatively poor mitogen for Balb/c3T3 cells in comparison to HB-EGF, it was similar in potency to HB-EGF in stimulating human prostate epithelial cell growth, suggesting that prostate epithelia may be a physiologic target for ARG in vivo. Expression of both ARG and KB-EGF mRNAs was induced in culture d prostate SMC by fibroblast growth factor-2, a human prostate SMC mitogen linked to prostate disease. These findings indicate that ARG and HB-EGF are likely to be key mediators of directional signaling between SMC and epithe lial. cells in the human prostate and appear to be coordinately regulated.