Evaluation of Androgen Receptor Function in Prostate Cancer Prognosis and Therapeutic Stratification.

摘要

While prostate cancers initially respond to androgen ablation therapy, tumors often become treatment resistant as tumor cells develop mechanisms to evade the treatment. Dysfunction of the androgen receptor frequently observed in castration resistant stages of prostate cancer. We reasoned that early knowledge of androgen receptor dysfunction can predict the course of prostate cancer progression. We proposed an approach for monitoring potential dysfunctions of the androgen receptor by measuring the expression of a panel of genes directly regulated by androgen receptor. We examined human prostate cancer tissues (surgery specimens) at early stages of the disease and matched with longitudinal follow up data. We have completed the evaluation of 140 patients by monitoring mRNA expression levels of ERG, PSA, PMEPA1, ODC1, AMT1 and GAPDH levels. Also, we have completed the evaluation of 80 whole-mounted sections of radical prostatectomy specimens by immunohistochemistry assessing AR, ERG, NKX3.1 and PSA proteins. This study addresses the association of AR function defects (decreased or attenuated expression of AR regulated genes) with unfavorable clinical features, as well as, if expression levels of the androgen regulated gene panel is indicative of biochemical recurrence- and metastasis-free survival. Major findings emerging from our PCRP/CDMRP award revealed that monitoring the levels of AR regulated proteins may support disease progression-associated clinical-pathologic features. In contrast, assessment of AR regulated genes at mRNA levels show promising performance in supporting the prediction of biochemical recurrence --free survival in low grade tumors. In summary, the study results indicate the utility of monitoring the defects of AR function in prostate cancer.