Amphiregulin Expression in Prostatic Intraepithelial Neoplasia and Adenocarcinoma: A Study of 93 Cases

BACKGROUND. Amphiregulin (AMP) is a heparin-binding glycoprotein that is structurally and functionally related to epidermal growth factor. Its effects are mediated by the tyrosine kinase activity of the epidermal growth factor receptor (EGF-R), and specific nuclear targeting sequences. AMP induces cell proliferation after androgen stimulation of human prostate cancer cell lines. An autocrine proliferative loop involving AMP, androgen, and EGF-R may, therefore, play a role in prostatic carcinogenesis. The purpose of this study was to compare the expression of AMP in benign prostatic epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. METHODS. We performed an immunohistochemical study of select sections from 93 radical prostatectomies performed at the Mayo Clinic between 1987 and 1991. All patients were previously untreated and found to have pathologic stage T2N0M0 adenocarcinoma after routine handling of surgical specimens. Affinity-purified polyclonal antibody directed against AMP was applied to tissue sections using the streptavidin-biotin method. For each case, the percentage of immunoreactive cells in benign epithelium, PIN, and adenocarcinoma was estimated in 10% increments. Intensity on a scale from 0 (negative) to 3 (strongly immunoreactive) and pattern of expression (nuclear versus cytoplasmic) also were recorded. RESULTS. AMP immunoreactivity was present in benign prostatic epithelium, PIN, and prostatic adenocarcinoma in all cases. The mean percentage of AMP-immunoreactive cells was 53.8% in benign epithelium, 65.9% in PIN, and 74.3% in cancer. Intensity was moderate in all cases. The pattern of expression was usually nuclear in benign epithelium (secretory and basal cells), and usually cytoplasmic or nuclear and cytoplasmic in PIN and adenocarcinoma. There were rare scattered immunoreactive cells in the stroma, ejaculatory duct epithelium, and urethral urothelium. Endothelial cells were invariably unstained. CONCLUSIONS. AMP expression in prostate increases progressively from benign epithelium to PIN and cancer. Increased expression of AMP may contribute to the development of prostatic adenocarcinoma. Predominantly nuclear staining was observed in benign epithelium, whereas cytoplasmic or nuclear and cytoplasmic staining was observed in PIN and adenocarinoma. The differences in nuclear and cytoplasmic localization of immunoreactivity may reflect the presence of two pathways of activation, and hence varying biological functions of AMP.