Expression of the Androgen Receptor in Prostate Tumor Models and Clinical Specimens

Among human PCA cell lines widely used, only LNCaP and MDA PCa 2a and 2b cells express AR. These cell lines are derived from PCA metastatic lesions (3,4). The reasons for AR down-regulation in other cell lines are not completely clear. It is assumed that some peptide hormones present in serum are responsible for down-regulation of the AR. For example, basic fibroblast growth factor is a potent inhibitor of AR expression (5). PC-3 and DU-145 cells, which do not express the AR, could be used for transient and stable transfections with AR cDNA. PC-3 cells stably transfected with the AR proliferate less rapidly than the cells transfected with an empty vector (6). Also, these cells are less invasive than their counterparts. AR expression is low in rat Dunning tumour sublines that rapidly metastasize (7). For this reason, it was believed for a long time that AR expression decreases during tumor progression. AR expression was studied with respective antibodies in clinical specimens obtained during endocrine therapy. From those studies, it was concluded that the AR is expressed in most prostate tumour specimens as well as in distant metastases obtained from patients who failed endocrine treatment (8,9). In LNCaP cells, AR mRNA is negatively regulated by androgen (10). However, androgenic hormones stabilize the protein, thus leading to increased expression of the AR following short-term treatment. Regulation of AR expression during long-term endocrine treatment is, however, different. Those cells adapt to an environment with low androgen supply and up-regulate AR mRNA and protein. Those findings were originally reported by Liao, et al. (11). They were confirmed by other researchers whose work led to the conclusion that PCA cells can overcome the effect of endocrine therapy by modulating AR expression. In one cell subline developed during prolonged steroid withdrawal, high AR activity was measured even in the absence of androgen (12). This increase in transcriptional activity ofthe AR could be in part explained by the influence of serum factors. To understand the cellular events in advanced PCA, it is important to emphasize that the AR in LNCaP derivatives established by long-term androgen ablation could be activated by much lower concentrations of androgens than the AR in parental LNCaP cells. The non-

steroidal anti-androgen bicalutamide caused small, but reproducible increase in reporter gene activity in long-term ablated cells. This was, however, sufficient for stimulation of growth in vitro and in vivo. The sequence of the AR in the hypersensitive subline, LNCaP-abl, was the same as that in parental LNCaP cells. There was no evidence for AR amplification in LNCaP-abl cells. Although the prostate-specific antigen gene is a classic example for an AR-regulated gene, its expression decreased in sublines developed after long-term androgen depletion. It was demonstrated that inhibition of expression of the AR in androgen-independent LNCaP sublines retards proliferation of those cells (13). This finding can have several consequences on development of novel clinical treatments for metastatic PCA.

AR expression increases in a subgroup of patients who underwent endocrine therapy due to amplification ofthe AR gene (14). Interestingly, some of these patients are better candidates for complete androgen ablation (orchiectomy or administration of luteinizing hormone releasing hormone analogues in combination with an anti-androgen) (15). In most cases, complete androgen withdrawal is not recommended for endocrine treatment since large clinical trials failed to show an advantage over orchiectomy or medical castration alone.

AR expression in PCA may be also elevated due to stabilization ofthe AR protein. This phenomenon was observed in the xenograft CWR 22 (16). This prostate tumour responds to castration by regression, but it relapses after some time. Expression ofAR-regulated genes also rebounds, thus indicating an important role for the AR in tumour progression.

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