Aberration in the expression of the retinoid receptor, RXRalpha, in prostate cancer.

There is ample evidence for a role for retinoids in the development and maturation of prostatic epithelium. In recent experiments with conditional disruption of a specific retinoid receptor, namely, RXRalpha in the prostatic epithelium of the mouse, we observed that a major component of retinoid action in the prostate is indeed mediated by RXRalpha. The results clearly indicated that the inactivation of RXRalpha in the prostate epithelium leads to the development of preneoplastic lesions (Huang et al. Cancer Res 62: 4812-9, 2002). To determine the relation of this finding to human prostate cancer, we examined the expression of RXRalpha protein in human prostate cancer cell lines by western blotting and prostate cancer specimens by immunohistochemistry. Relative to the "normal" prostate epithelial cells, there was approximately two- to nine-fold decrease in the full-length 54 kD RXRalpha protein in each of the seven different prostate cancer cell lines tested. Similarly, while RXRalpha immunostaining was uniformly strong in the nuclei of most of the benign prostatic epithelial cells of the thirteen adenocarcinoma specimens tested, a highly heterogeneous pattern of expression was detected in the malignant epithelium, with some areas with low or no staining, others with mostly cytoplasmic staining, and some with both nuclear and cytoplasmic immunoreactivity. To evaluate the effect of RXRalpha modulation on the biologic properties of prostate cancer cell lines, we used a lentivirus expression system to overexpress RXRalpha in CWR22R prostate cancer cells that basally expressed a marginal level of the receptor. The sorted RXRalpha-transduced cells were compared to the corresponding vector control cells for proliferative and apoptotic properties. A correlation of reduction of cell growth or increased susceptibility to apoptosis with increases in the level of RXRalpha nuclear receptor was demonstrated. These effects were further enhanced when the cell culture medium was supplemented with a retinoid receptor panagonist, 9-cis retinoic acid. Together, these data support the notion that, like in mouse prostate, loss or reduction of RXRalpha activity might be a critical factor in prostate tumorigenesis in humans.