Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary andmetastatic carcinoma

An antibody, GC-17, thoroughly characterized for its specificity for estrog en receptor-beta (ER-beta), was used to immunolocalize the receptor in hist ologically normal prostate, prostatic intraepithelial neoplasia, primary ca rcinomas, and in metastases to lymph nodes and bone. Comparisons were made between ER-beta, estrogen receptor-alpha (ER-alpha), and androgen receptor (AR) immunostaining in these tissues. Concurrently, transcript expression o f the three steroid hormone receptors was studied by reverse transcriptase- polymerase chain reaction analysis on laser capture-microdissected samples of normal prostatic acini, dysplasias, and carcinomas. In Western blot anal yses, GC-17 selectively identified a 63-kd protein expressed In normal and malignant prostatic epithelial cells as well as in normal testicular and pr ostatic tissues. This protein Likely represents a posttranslationally modif ied form of the long-form ER-beta, which has a predicted size of 59 kd base d on polypeptide length. In normal prostate, ER-beta Immunostaining was pre dominately localized in the nuclei of basal cells and to a lesser extent st romal cells. ER-alpha staining was only present in stromal cell nuclei. AR immunostaining was variable in basal cells but strongly expressed in nuclei of secretory and stromal cells. Overall, prostatic carcinogenesis was char acterized by a loss of ER-beta expression at the protein and transcript lev els in high-grade dysplasias, its reappearance in grade 3 cancers, and its diminution/absence in grade 4/5 neoplasms. In contrast, AR was strongly exp ressed in all grades of dysplasia and carcinoma. Because ER-beta is thought to function as an inhibitor of prostatic growth, androgen action, presumab ly mediated by functional AR and unopposed by the beta receptor, may have p rovided a strong stimulus for aberrant cell growth. With the exception of a small subset of dysplasias in the central zone and a few carcinomas, ER-al pha -stained cells were not found in these lesions. The majority of bone an d lymph node metastases contained cells that were immunostained for ER-beta . Expression of ER-beta in metastases may have been influenced by the local microenvironment in these tissues. In contrast, ER-alpha -stained cells we re absent in bone metastases and rare in lymph nodes metastases, Irrespecti ve of the site, AR-positive cells were found in all metastases. Based on ou r recent finding of anti-estrogen/ER-beta -mediated growth inhibition of pr ostate cancer cells in vitro, the presence of ER-beta in metastatic cells m ay have important implications for the treatment of late-stage disease.