Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Abstract

Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (AR v567es ) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, AR v567es functioned as a constitutively active receptor, increased expression of full-length AR (AR fl ), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with AR v567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of AR v567es to AR fl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected AR v567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

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

“…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]. Thus, polymorphisms that change this peptide sequence would be expected to have potential impact on ARV biological function.…”

“…Most ARVs have been shown to be constitutively (AR-V3, -V4, -V7, and -V12) [9,10,12,17] or conditionally (AR-V1 and -V9) [10,12] active androgen-independent transcription factors in a prostate cancer context. Pre-clinical and clinical studies have supported the concept that ARVs are biologically relevant in prostate cancer, particularly in the genesis of a CRPC [11,12,[17][18][19][20].…”

Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

“…Mutations in the AR gene may change its ligand binding characteristics or its transcriptional activity, resulting in the modulation of its target gene expression (Brooke et al 2008, Brooke & Bevan 2009). In addition to AR mutations, several AR splice variants that exhibit transcriptional activity even in the absence of androgen and contribute to the promotion of CRPC have recently been identified (Dehm et al 2008, Guo et al 2009, Hu et al 2009, Sun et al 2010, Watson et al 2010. Although a relationship between AR splice variants and oxidative stress has not been reported to date, it is possible that oxidative stress may be implicated in the expression of AR splice variants as it is for splice variants of other genes (Xu & Chu 2007, Soliman et al 2009, Takeo et al 2009.…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…AR transcriptional activity also increases in response to higher levels of MAGE-A11, which has been observed in ϳ36% of castration-resistant prostate cancers (1, 2). Here we show that ARF interferes with the stimulatory effects of MAGE-A11 on androgen-dependent AR transcriptional activity and the constitutive activity of a splice-variant-like AR reported in prostate cancer (47)(48)(49). The findings suggest that the inhibitory effects .…”

“…A similar analysis was performed on the constitutive activity of AR-(1-660) NH 2 -terminal and DNA-binding fragment that lacks the ligand binding domain and mimics AR splice variants reported in prostate cancer (47)(48)(49). ARF inhibited the constitutive activity of AR-(1-660) with or without expression of MAGE-A11 (Fig.…”