Androgen receptor splice variants and prostate cancer: From bench to bedside.

Kristine M Wadosky,Shahriar Koochekpour

doi:10.18632/oncotarget.14537

Abstract

Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing. These AR splice variants are increased in cell and mouse models of CR-PCa and in CR-PCa tumors. Several AR variants lack the ligand binding domain, but retain their ability to bind DNA and activate transcriptionlinking constitutive AR function and therapeutic failure. ARV7 is the only variant endogenously detected at the protein level and thus has undergone more thorough molecular characterization. Clinical trials in PCa are currently investigating ARV7 utility as a biomarker and new therapeutics that inhibit ARV7 . Overall, this review will illustrate the historical perspectives of AR splice variant discovery using fundamental molecular biology techniques and how it changed the clinical approach to both therapeutic decisions and strategy. The body of work investigating AR splice variants in PCa represents a true example of translational research from bench to bedside.

Highlights

Prostate cancer (PCa) is the leading diagnosed noncutaneous cancer among men in the United States, as estimated by the American Cancer Society in 2016 [1]
While this study did not apply methods standard to the field of in vivo prostate cancer (PCa) research, these data show that mRNA expression of Androgen receptor variant (ARV) in human xenografts established in the prostatic microenvironment are increased following development of androgen deprivation therapy (ADT) resistance [65]
The progression of evidence surrounding the role of ARVs in development of resistance to ADT in PCa represents a true example of translational uro-oncology research

Summary

Introduction

Prostate cancer (PCa) is the leading diagnosed noncutaneous cancer among men in the United States, as estimated by the American Cancer Society in 2016 [1]. To determine the ability of ARV7 to activate endogenous transcription, Hu et al overexpressed ARV7 in LNCaP cells and performed a gene expression microarray for ARGs [44]. Another study confirmed these data using quantitative RT-PCR to show that overexpression of ARV7 in LNCaP cells activates transcription of TMPRSS2 and FKBP51 in the absence of androgen stimulation [48].

Results

Conclusion