Malignant Transformation of Human Prostatic Epithelium Is Associated with the Loss of Androgen Receptor Immunoreactivity in the Surrounding Stroma 1 E. Oluwabunmi Olapade-Olaopa, 2 E. Hugh MacKay, Nicholas A. Taub, Davinder P. S. Sandhu, Timothy R. Terry, and Fouad K. Habib Departments of Urology [E. O. O-O., D. P. S. S., T. R. T.] and Pathology [E. H. M.], Leicester General Hospital, Leicester LE5 4PW; Department of Epidemiology and Public Health, University of Leicester, Leicester LE1 6TP [N. A. T.]; and University Department of Surgery, Western General Hospital, Edinburgh EH4 2XU [F. K. H.], United Kingdom ABSTRACT The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expres- sion in the progression of prostatic tumors have been incon- clusive. Androgenic influence over prostatic growth is me- diated via the regulation of interactions between stromal and epithelial cells. We hypothesized that neoplastic trans- formation of the prostate would be associated with alter- ations in hAR expression in the adjacent stroma. Using immunohistochemical techniques, we determined hAR pos- itivity in the epithelium and adjacent stroma of sections from 17 benign and 39 malignant prostatic glands. We found that whereas the expression of the receptor decreased in both cellular compartments as the tissues dedifferentiated, the depletion was more pronounced in the stromal nuclei (P < 0.0001). However, in sections from both untreated and hormone-resistant prostate cancer tissues, although hetero- geneity of hAR expression in malignant epithelia was in- creased, there appeared to be a unique field effect around the cancerous prostate glands that resulted in a decreased expression of the receptor in the adjacent benign glands and its total loss in the surrounding stroma. The loss of hAR in the stroma adjacent to malignant prostatic epithelium may play an important role in prostate cancer progression. Fur- thermore, the similarity of the lack of stromal hAR expres- sion in newly diagnosed and hormone-resistant prostate can- cer (P  0.85) may be an indication that the mechanisms responsible for the acquisition of hormone independence are established early in the malignant transformation process. INTRODUCTION Androgenic control over the normal growth and differen- tiation of the prostate gland is transmitted via hARs 3 that are expressed by the nuclei of both stromal and epithelial cells (1). The mechanisms responsible for the initiation and propagation of prostatic carcinogenesis and the development of hormone resistance in CAP are still unknown, but abnormalities in the activity of these steroid receptors are thought to play an impor- tant part in these changes in the prostatic cell phenotype. As a result, evaluation of hAR expression in normal and abnormal prostatic tissues has been a major focus of efforts to unravel the mechanisms responsible for malignant transformation and hormone-independent growth of the organ. In the earliest studies, hAR content of prostatic tissues was assessed using biochemical assays, but these studies were con- sidered nonspecific because the substrates analyzed were a heterogeneous mixture of stromal elements and benign and malignant epithelial cells (2). The recent development of anti- hAR-specific antibodies has made it possible to determine hAR expression in the individual glands and cellular compartments within prostatic tissue sections. Studies using this newer meth- odology have concentrated mainly on the tumor cells and have reported conflicting findings. Whereas initial reports suggested that hAR protein expression in epithelial nuclei was inversely proportional to the histological grade of the tissues (3, 4), more recent studies have detected high expression and increased heterogeneity of the receptor in advanced cancers (5, 6). These later reports are supported by scrutiny of prostate cancer tissues using reverse transcriptase techniques, which has revealed am- plification of the hAR gene in hormone-refractory tumors (7, 8). hAR transmission of hormonal control of prostatic growth occurs via the regulation of the expression of the peptide growth factors and receptors involved in the stromal-epithelial interac- tions that mediate the influence of androgens on the gland (9, 10). Proliferation and differentiation of prostatic epithelium is initiated by the binding of epithelial cell membrane receptors by growth factors expressed by stromal cells (11). This intercellular relationship indicates that prostatic stroma plays an important intermediary role in the transmission of androgen-induced stim- Received 6/26/98; revised 9/25/98; accepted 12/8/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work is dedicated to Prof. T. F. Solanke (contemporary). These results were presented in part at the British Association of Urological Surgeons Meeting in Bournemouth, United Kingdom, June 21–24, 1997 and at the Schilling Research Conference, Hormones and Cancer in Santa Cruz, California, September 18 –21, 1997. 2 To whom requests for reprints should be addressed, at Department of Urology, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, United Kingdom. 3 The abbreviations used are: hAR, human androgen receptor; CAP, carcinoma of the prostate; BPH, benign prostatic hyperplasia; HG, high grade; PIN, prostatic intraepithelial neoplasia. 569 Vol. 5, 569 –576, March 1999 Clinical Cancer Research