Increased expression of genes converting adrenal androgens to testosterone in castration-recurrent prostate cancer

Abstract

Androgen deprivation is still the standard systemic therapy for locally advanced or metastatic prostate cancer (PCa), but patients invariably relapse with a more aggressive form of PCa that has been termed castration-recurrent PCa (CRPCa). The androgen receptor (AR) is expressed at high levels in most cases of CRPCa, and these tumors resume their expression of multiple AR regulated genes, which indicates that AR transcriptional activity becomes reactivated at this stage of the disease. Mechanisms that may contribute to AR reactivation in CRPCa include increased AR protein expression, AR mutations, increased expression of transcriptional coactivator proteins, and activation of signal transduction pathways that can enhance AR responses to low levels of androgens. Recent data indicate that a further mechanism for AR reactivation in CRPCa cells may be through increased intracellular synthesis of testosterone and 5α-dihydrotestosterone (DHT). The enzymes that mediate androgen synthesis and metabolism in normal prostate and in PCa, and evidence indicating that their increased expression contributes to the development of CRPCa, are outlined in this chapter. The early use of therapies that more aggressively block androgen production may enhance responses to androgen deprivation therapy, and prevent or delay the adaptations that eventually lead to CRPCa. © 2009 Springer-Verlag New York.