Endocrine Abstracts

The androgen receptor (AR) functions as a master transcriptional regulator of prostate tissue homeostasis. This master transcriptional regulator function is maintained in prostate cancer. Therefore, prostate cancer is an androgen-dependent disease and suppression of AR transcriptional activity with androgen deprivation therapy (ADT) is an effective systemic therapy. However, development of therapy resistance and transition to castration resistant prostate cancer (CRPC) represents a major clinical challenge. One mechanism by which CRPC may circumvent ADT is by expression of constitutively active AR variants (AR-Vs) that lack the ligand binding domain. The best-studied AR-V is AR-V7, but a controversy in the field is that AR-V7 is broadly expressed and readily detectable in AR-expressing tissues, including normal prostate. To address this controversy, we have been elucidating mechanisms governing the expression of AR-Vs in prostate cancer, with the goal of identifying clinically-relevant contexts in which they may be functioning as drivers of resistance. These studies have revealed heterogeneous, clonally diverse AR gene rearrangements in clinical CRPC. Investigation of several AR gene rearrangement events has demonstrated they converge functionally by driving stable, outlier expression of diverse tumor-specific AR-V species that are functionally equivalent to AR-V7 but undetectable by AR-V7-specific assays currently under clinical development. A second mechanism of AR-V expression is alternative polyadenylation, whereby AR-V7 is co-ordinately expressed in CRPC tissues with AR-V9, AR-V1, and other annotated AR-Vs. This indicates that detection of AR-V7 in CRPC tissue or circulating tumor cells is likely a harbinger of a broader repertoire of AR-V expression. Studies are underway to translate this knowledge to biomarker applications for prostate cancer patients, and also for development of new therapies to combat AR-Vs.

DOI: 10.1530/endoabs.54.IS7