Alternatively spliced androgen receptor variants

Abstract

Alternative splicing is an important mechanism for increasing functional diversity from a limited set of genes. De-regulation of this process is common in diverse pathologic conditions. The androgen receptor (AR) is a steroid receptor transcription factor with functions critical for normal male development as well as the growth and survival of normal and cancerous prostate tissue. Studies of AR function in androgen insensitivity syndrome (AIS) and prostate cancer (PCa) have demonstrated loss-of-function AR alterations in AIS, and gain-of-function AR alterations in PCa. Over the past two decades, AR gene alterations have been identified in various individuals with AIS, which disrupt normal AR splicing patterns and yield dysfunctional AR protein variants. More recently, altered AR splicing patterns have been identified as a mechanism of PCa progression and resistance to androgen-depletion therapy. Several studies have described the synthesis of alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the ultimate target of androgen depletion. Many of these truncated AR isoforms function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as the androgen-independent growth of PCa cells. In this review, we will summarize the various alternatively spliced AR variants that have been discovered, with a focus on their role and origin in the pathologic conditions of AIS and PCa.

Identification of Androgen Receptor Splice Variant Transcripts in Breast Cancer Cell Lines and Human Tissues

“…As discussed earlier, many ARVs (V1, V4, V5, V6, V7, and V9) share the NTD/DBD domains encoded by canonical exons 1-3 [10,35]. The C-terminal short peptide of 1-53 amino acids encoded by the cryptic exons is the only structural difference that would contribute to their reported varying capacity for transcriptional activity [17,30] and differing cellular localization [9,10,12,30].…”

“…In the current study, we provide evidence for the first time that C-terminal truncated ARVs recently discovered in prostate cancer cells are also expressed in breast cancer cell lines and in multiple human tissues. Importantly, if expression of these ARVs is demonstrated at the protein level, in particular in response to AR targeted therapies as has been reported in prostate cancer [35], expression of ARVs may have relevance for women with breast cancer currently being treated with similar AR-targeted therapies as in the clinical trials cited above. One of the significant discoveries to arise from the EN-CODE project [36] is that the large majority of human genes exhibit some degree of alternative splicing; up to 25 splice variants commonly arise from a single gene in addition to the wild type transcript.…”

“…Among these, mutations in the AR gene that result in abnormal splicing events have long been known to cause some cases of androgen insensitivity syndrome (AIS) [32][33][34]. However, the association between a disease state and alternative splicing from the wild type AR gene or aberrant splicing due to genomic rearrangements have been very recent discoveries and so far confined to the field of prostate cancer, where the AR has an indisputable role as an oncogene [14,15,19,35]. The AR splice variants expressed in advanced prostate cancer are largely hormone independent transcription factors that contribute to the maintenance of AR signalling in an androgendeplete environment and are resistant to conventional antiandrogenic drugs as they lack a ligand binding domain, the docking site for these drugs.…”

“…Androgen deprivation therapy for prostate cancer aims to inhibit classical ligand-mediated AR signalling, which requires an intact ligand binding domain. This treatment can select for ARVs that lack the LBD and are constitutively active, thus sustaining or resurrecting AR signalling in an androgen deplete environment or in the presence of anti-androgens [35,37]. Based on evidence from preclinical studies that the AR can drive growth of a molecular subtype of breast cancer called molecular apocrine [38] or luminal androgen receptor (LAR) breast cancers [39], various forms of ADT (bicalutamide, enzalutamide, abiraterone) are currently in phase I/II clinical trials to examine the efficacy of treating women with ER-negative/AR-positive metastatic breast cancers with agents that repress classical ligandmediated AR-signall ing (see clinicaltrials.gov: NCT00468715, NCT01597193, and NCT00755885).…”

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

“…22Rv1 is a model of CRPC that expresses WT PTEN, full-length mutated AR, and constitutively active AR splice variants (42,43). The growth of 22Rv1 depends on the presence of these AR splice variants (44)(45)(46).…”