Investigating the role of constitutively active truncated androgen receptor splice variants in prostate cancer

Abstract

The androgen receptor (AR) is fundamental for the growth and survival of normal and malignant prostate cells. Therefore, androgen deprivation therapy remains the first‐line treatment for disseminated disease, however, relapse and progression to a castration‐resistant phenotype for which no durable treatment currently exists, is inevitable. Unequivocal evidence now exists that restored AR activity is fundamental in the progression to castration‐resistant prostate cancer (CRPC). Multiple mechanisms by which AR is reactivated under androgen‐depleted conditions may be involved in the development of this lethal phenotype. Recent studies have identified alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand‐binding domain which is the therapeutic target of androgen deprivation therapy. Many of these truncated AR variants function as constitutively active, ligand‐independent transcription factors that can support androgen‐independent expression of AR target genes, as well as ligand independent growth of prostate cancer cells. In this study, an AR variant gene signature independent of full‐length AR consisting of 284 genes was identified in the 22Rv1 cell‐based model of CRPC using whole‐genome microarray. The clinical relevance of this AR variant gene signature was also determined in a cohort of prostate cancer specimens with the AR variant gene signature sufficient to distinguish between microdissected benign and malignant prostate cancer specimens. Furthermore, a number of putative AR variant regulated pro‐oncogenes (TAX1BP1, NRP1, LEF1, LAMP3, IGFBP3) and tumor suppressor genes (SPRY2, RASD1, MBP, BNIP3L), upregulated and downregulated respectively with disease progression and biochemical recurrence were identified. These findings may provide a critical insight into the mechanism of disease progression mediated by truncated AR variants and reveal potential targets for therapeutic intervention in patients who progress despite androgen deprivation therapy.