Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy

Abstract

The majority of prostate cancers (PCa) express high levels of androgen receptor (AR) and are dependent for their growth on testosterone produced by the testes, which is reduced in the prostate to the higher affinity ligand 5α-dihydrotestosterone (DHT). PCa growth can be suppressed by androgen deprivation therapy, which involves removal of testicular androgens (surgical or medical castration) or treatment with an AR antagonist (or a combination of both), but patients invariably relapse with tumors that have been termed castration recurrent/resistant PCa (CRPC). Importantly, AR transcriptional activity becomes reactivated at this CRPC stage of the disease and remains essential for tumor growth. The objective of this review is to outline one clinically important mechanism contributing to this AR reactivation, which is increased intratumoral synthesis of testosterone and DHT from weak androgens produced by the adrenal glands and possibly de novo from cholesterol. Early studies showed that a substantial fraction of CRPC patients responded to adrenalectomy or medical suppression of adrenal androgen synthesis using agents such as ketoconazole (CYP17A1 inhibitor), and a recent phase III study of a more potent and selective CYP17A1 inhibitor (abiraterone) has demonstrated an improvement in survival. With the pending FDA approval of abiraterone for CRPC, defining the molecular mechanisms contributing to CYP17A1 inhibitor resistance/relapse and AR reactivation is now critical to build on these advances.

Figure 1

Outline of steps mediating androgen synthesis and metabolism in prostate cancer cells. Pathways that may contribute to androgen synthesis in prostate are outlined. Bold arrows and brackets outline what appears to be the major pathway for generation of testosterone and DHT in PCa cells after ADT when adrenal synthesis of weak androgens is intact and there are high levels of circulating DHEA-S. PCa cells can also synthesize at least trace amounts of testosterone directly from cholesterol through the sequential actions of CYP11A1, CYP17A1, HSD3B1 or 2, and AKR1C3 through the pathway that is normally active only in the adrenal glands and testes (also shown in brackets). It should be noted that testes uses 17β-hydroxysteroid dehydrogenase type 3 rather than AKR1C3 to generate testosterone (not shown). A possible alternative ‘backdoor’ pathway is also shown that may bypass testosterone and generate DHT from androsterone. In some cases more than one enzyme can carry out a particular step (HSD3B1 or HSD3B2; AKR1C2 or AKR1C3; and SRD5A1 or SRD5A2). Inhibitors of enzymes in the pathways are also indicated.