The development of prostatic intraepithelial neoplasia (PIN)-like lesions in the prostate-specific retinoid X receptor-alpha (RXRalpha) null mouse suggests that RXRalpha may protect against neoplasia. The purpose of this study was to characterize RXRalpha protein expression in human prostate to determine if RXRalpha is altered in early stages of tumor progression. Immunohistochemistry with anti-RXRalpha antibody was performed on 138 fresh frozen prostate specimens collected from 27 noncarcinomatous prostates and 111 radical prostatectomy samples of prostate adenocarcinoma (CA). The RXRalpha signal intensity was scored using a scale of 0-3. In normal glands, RXRalpha was expressed strongly in basal cells and only weakly in secretory epithelial cells. This finding was confirmed by double immunofluorescence labeling of RXRalpha and Keratin-903, a basal cell marker, followed by confocal microscopic examination. In basal cells, a gradual decrease of RXRalpha 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 RXRalpha in basal cells, only 48% (13 of 27) of the high-grade PIN glands appeared positive. Moreover, basal cell expression of RXRalpha 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 RXRalpha 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.