The androgen receptor (AR) is a master regulator transcription factor in normal and cancerous prostate cells.
Canonical AR activation requires binding of androgen ligand to the AR ligand binding domain, translocation to the nucleus,
and transcriptional activation of AR target genes. This regulatory axis is targeted for systemic therapy of advanced
prostate cancer. However, a new paradigm for AR activation in castration-resistant prostate cancer (CRPC) has emerged
wherein alternative splicing of AR mRNA promotes synthesis of constitutively active AR variants that lack the AR ligand
binding domain (LBD). Recent work has indicated that structural alteration of the AR gene locus represents a key mechanism
by which alterations in AR mRNA splicing arise. In this review, we examine the role of truncated AR variants
(ARVs) and their corresponding genomic origins in models of prostate cancer progression, as well as the challenges they
pose to the current standard of prostate cancer therapies targeting the AR ligand binding domain. Since ARVs lack the
COOH-terminal LBD, the genesis of these AR gene rearrangements and their resulting ARVs provides strong rationale
for the pursuit of new avenues of therapeutic intervention targeted at the AR NH2-terminal domain. We further suggest
that genomic events leading to ARV expression could act as novel biomarkers of disease progression that may guide the
optimal use of current and next-generation AR-targeted therapy.
Keywords: Androgen receptor, alternative splicing, castration resistance, genomic rearrangement, prostate cancer
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