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Decreased Retinoid X Receptor- Protein Expression in Basal Cells Occurs in the Early Stage of Human Prostate Cancer Development

¹ Department of Epidemiology, School of Public Health; Departments of ² Urology and ³ Pathology, School of Medicine and ⁴ Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA; and Departments of ⁵ Pathology, ⁶ Surgery, and ⁷ Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Requests for reprints: Jianyu Rao, M.D., Department of Pathology and Lab Med, David Geffen School of Medicine, UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095. Phone: (310) 794-1567; Fax: (310) 825-7795. E-mail: jrao{at}mednet.ucla.edu

The development of prostatic intraepithelial neoplasia (PIN)-like lesions in the prostate-specific retinoid X receptor- (RXR) null mouse suggests that RXR may protect against neoplasia. The purpose of this study was to characterize RXR protein expression in human prostate to determine if RXR is altered in early stages of tumor progression. Immunohistochemistry with anti-RXR antibody was performed on 138 fresh frozen prostate specimens collected from 27 noncarcinomatous prostates and 111 radical prostatectomy samples of prostate adenocarcinoma (CA). The RXR signal intensity was scored using a scale of 0–3. In normal glands, RXR was expressed strongly in basal cells and only weakly in secretory epithelial cells. This finding was confirmed by double immunofluorescence labeling of RXR and Keratin-903, a basal cell marker, followed by confocal microscopic examination. In basal cells, a gradual decrease of RXR expression was noted from normal glands of noncarcinomatous prostate (3.0 ± 0) to "normal" glands distant to CA (2.13 ± 0.44) to "normal" glands adjacent to CA (1.25 ± 0.53) and high-grade PIN (0.56 ± 0.58). While nearly all "normal" glands from 138 specimens were positive for RXR in basal cells, only 48% (13 of 27) of the high-grade PIN glands appeared positive. Moreover, basal cell expression of RXR in "normal" tissue was less in specimens with poorly differentiated tumor (Gleason score 8; 1.83 ± 0.36) compared with well-differentiated tumor (Gleason score < 6; 2.35 ± 0.34; P = 0.04). Thus, a decrease of RXR in the basal cells may serve as a marker for prostate CA-associated field change, which may represent an early event in the prostate carcinogenic process. These findings suggest that chemoprevention strategies with retinoids may be most effective if applied during the early stages of transformation.

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