June 1, 2021

The role of androgen receptor variant AR-V9 in prostate cancer

Author(s): Ho, Yeung and Van Etten, Jamie L. and Henzler, Christine and Yang, Rendong and Li, Yingming and Tseng, Elizabeth and Hon, Ting and Clark, Tyson and Dehm, Scott

The expression of androgen receptor (AR) variants is a frequent, yet poorly-understood mechanism of clinical resistance to AR-targeted therapy for castration-resistant prostate cancer (CRPC). Among the multiple AR variants expressed in CRPC, AR-V7 is considered the most clinically-relevant AR variant due to broad expression in CRPC, correlations of AR-V7 expression with clinical resistance, and growth inhibition when AR-V7 is knocked down in CRPC models. Therefore, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The aim of this study was to understand whether other AR variants are co-expressed with AR-V7 and promote resistance to AR-targeted therapies. To test this, we utilized RNA-seq to characterize AR expression in CRPC models. RNA-seq revealed the frequent coexpression of AR-V9 and AR-V7 in multiple CRPC models and metastases. Furthermore, long-read single-molecule real-time (SMRT) sequencing of AR isoforms revealed that AR-V7 and AR-V9 shared a common 3’terminal cryptic exon. To test this, we knocked down AR-V7 in prostate cancer cell lines and confirmed that AR-V9 mRNA and protein expression were also impacted. In reporter assays with AR-responsive promoters, AR-V9 functioned as a constitutive activator of androgen/AR signaling. Similarly, infection of AR-V9 lentiviral construct in LNCaP cells induced androgen-independent cell proliferation. In conclusion, these data implicate co-expression of AR-V9 with AR-V7 as an important component of constitutive AR signaling and therapeutic resistance in CRPC.

Organization: University of Minnesota
Year: 2018

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