Lessons from tissue compartment-specific analysis of androgen receptor alterations in prostate cancer. Issue 166 (February 2017)

• Record Type: Journal Article
• Authors: Daniel, Mark; Dehm, Scott M.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 166(2017)
• Page Start: 28
• Page End: 37
• Publication Date: 2017-02
• Subjects: LHRH luteinizing hormone releasing hormone -- ADT androgen depletion therapy -- CRPC castration-resistant prostate cancer -- CYP17 cytochrome P450 c17 -- MR mineralocorticoid receptor -- ER estrogen receptor -- PR progestins receptor -- GR glucocorticoid receptor -- NTD NH2-terminal domain -- AF-1 activation function 1 -- LBD ligand bind domain -- ARE androgen response element -- RIP RNA co-immunoprecipitation -- NCOA nuclear receptor coactivator -- NCOR nuclear receptor corepressor -- CTC circulating tumor cell -- ctDNA circulating tumor DNA -- FISH fluorescence in situ hybridization -- PSA prostate-specific antigen -- PMSA prostate-specific membrane antigen; Androgen receptor splice variant -- Prostate cancer -- Castration-resistant prostate cancer -- Circulating tumor cell; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.04.016
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Reactivation of androgen receptor is critical in prostate cancer disease progression. Androgen receptor splice variants lack the COOH-terminal ligand binding domain rendering them constitutively active in the absence of ligand. Androgen receptor splice variant transcripts are detectable in multiple tissue compartments. Androgen receptor splice variant-7 may serve as a predictive biomarker for patients treated with androgen receptor targeted therapies. Abstract: Androgen receptor (AR) splice variants (AR-Vs) are constitutively active transcription factors that function in the absence of ligand. AR-Vs represent one of several AR re-activation mechanisms utilized by prostate cancer to circumvent first-line androgen deprivation therapy. Second line therapies such as enzalutamide and abiraterone are treatments that re-target components of the androgen/AR axis. However, these second line therapies do not benefit all patients, and patients that do receive initial benefit can develop resistance rapidly. Alterations in components of the androgen/AR axis, including expression of AR-Vs, appear to be linked to primary as well as secondary resistance to second line therapies. However, some key conclusions appear to differ depending on the tissue compartment and measurement platform utilized for analysis. In this review, alterations in AR and the broader AR pathway will be examined in the context of primary prostate cancer tissue, metastatic castration-resistant prostate cancer tissue, circulating tumor cells, and circulating cell-free tumor DNA. Questions regarding the utility of AR-V measurements to provide prognostic information or predict patient responses to AR-targeted therapies will be addressed.