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Altered Expression of Androgen Receptor in the Malignant Epithelium and Adjacent Stroma Is Associated with Early Relapse in Prostate Cancer¹

Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia [S. M. H., D. I. Q., D. R. H., R. L. S.]; Department of Anatomical Pathology, Royal Prince Alfred Hospital, and Department of Pathology, University of Sydney, Camperdown, New South Wales 2050, Australia [C. S. L.]; Departments of Urology [D. G., P. C. B., P. D. S.] and Medical Oncology [J. J. G.], St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia; and Douglass Hanly Moir Pathology, North Ryde, New South Wales 2113, Australia [W. D.]

The molecular basis of androgen-independent prostate cancer is unknown; however, functional androgen receptor (AR) signaling is maintained after the acquisition of hormone-refractory disease. Because normal and malignant prostate epithelial cell proliferation is regulated by androgen stimulation via both the AR-positive stroma and epithelium, we sought to evaluate patterns of AR expression in these cells and to determine any relationships with prostate cancer progression. AR expression in the malignant epithelium and associated periepithelial and nonperiepithelial stroma was measured in a cohort of 96 patients with clinically localized prostate cancer treated with radical prostatectomy. Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model with other variables of known clinical relevance, including Gleason score, pathological stage, clinical stage, and pretreatment prostate-specific antigen concentration. Concurrent overexpression of AR (70% positive nuclei) in the malignant epithelium and loss of AR immunoreactivity in the adjacent periepithelial stroma (30%) was associated with higher clinical stage (P = 0.01), higher pretreatment prostate-specific antigen level (P = 0.03), and earlier relapse after radical prostatectomy (log-rank P = 0.009). These data identify a pattern of AR expression in malignant epithelium and adjacent stroma that is associated with a poor clinical outcome in prostate cancer. Equally important, they identify the need to further investigate the mechanistic basis of loss of AR expression in the malignant stroma and its potential role in deregulation of prostate epithelial cell proliferation.

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