Androgen Receptor And Localized Disease

The role of AR in the progression of clinically localized prostate cancer has only recently been addressed.103,104 Henshall et al.103 reported that AR was expressed in more than 70% of the tumor cells in localized prostate cancer but that there was loss of AR immunoreactivity in the ad jacent peritumoral stroma, which was associated with earlier relapse after radical prostatectomy. Sweat et al.104 found no association between AR expression and disease progression in a highly selected cohort of tumors with a Gleason score of 6-9. In our laboratory, the level of AR protein in tumor foci determined by video image analysis was a strong predictor of the risk of relapse following radical prostatectomy (unpublished observations). While further studies are necessary to determine how AR influences disease progression in clinically localized prostate cancer, a number of mechanisms have been identified in prostatic tumors that potentially explain the increase in levels of AR immunostain-ing observed in tumor cells in our study. These mechanisms include amplification of the AR gene,106 changes in the methylation status of the AR promoter and hence transcription of the AR gene,107,108 altered stability of AR mRNA,109 and ligand-independent activation of the receptor.9,110 Irrespective of the mechanism, increased AR levels likely result in altered expression profiles of androgen-regulated proteins, including angiogenic factors, cell adhesion molecules, and cell cycle regulators (e.g., vascular endothelial growth factor, integrins, and CDKs and their inhibitors,111-113) which could collectively contribute to disease progression.

Was this article helpful?

0 0

Post a comment