A role for the androgen-receptor in clinically localized and advanced prostate cancer

Abstract

Earlier studies of androgen-receptor (AR) expression using frozen prostate tissue, and later studies using archived specimens, produced the consensus that ligand-stabilized AR is nuclear, AR expression is similar in benign epithelia and stroma, AR expression is greater in secretory epithelia than basal cells, and AR expression is more variable in prostate cancer (CaP) than in benign prostatic hyperplasia (BPH). Accurate measurement of AR expression remains technically challenging but necessary to evaluate the relevance of ARs to clinical CaP. Recent studies demonstrated that AR expression in epithelia and stroma may be prognostic in clinically localized CaP, and AR expression may play a role in racial differences in CaP mortality and predict response to androgen deprivation therapy. High levels of AR and AR-regulated gene expression indicate a central role for AR in growth regulation of castration-recurrent CaP. New treatments for the lethal phenotype of CaP require better understanding of AR transactivation during androgen deprivation therapy. Keywordsandrogen receptor; prostate cancer; quantitative video image analysis; immunohistochemistry Androgens are necessary for the development and growth of the prostate and for the development, growth and progression of prostate cancer (CaP). An American man is diagnosed with CaP every 3 minutes,[1] and the worldwide incidence of CaP is increasing an estimated 1.1% annually.[2] Despite increased use of digital rectal examination and serum prostatespecific antigen (PSA) measurement for early detection, approximately 30% of men treated with curative intent suffer CaP recurrence. These men, and those who present with locally advanced or metastatic CaP, can be palliated by androgen deprivation therapy (ADT), which causes regression of androgen-dependent CaP through programmed cell death.[3] Although there are many methods for medical and surgical ADT, the results of ADT remain unimproved since its discovery more than 60 years ago.[4] More than 80% of men with disseminated CaP demonstrate clinical or biochemical response that is associated with a mean life expectancy of approximately 3.5 years, in contrast to non-responders or untreated patients who live an average of 9 months. Regardless of the androgen responsiveness of incurable CaP, almost all patients succumb to castration-recurrent CaP because it responds poorly to all known therapies, and

The hallmarks of castration-resistant prostate cancers

“…DHEA could be converted to androstenedione, a substrate for conversion to testosterone. The expression of all the genes necessary for synthesizing androgens are described to be increased in CRPC compared to early PC analyzed from untreated patients [9,25,28,29]. Among the recently developed drugs, abiraterone acetate is an inhibitor of CYP17A, an enzyme involved in the intratumoral androgen biosynthesis.…”

KU675, a Concomitant Heat-Shock Protein Inhibitor of Hsp90 and Hsc70 that Manifests Isoform Selectivity for Hsp90α in Prostate Cancer Cells

“…The level of expression of Hsp90 client proteins has been shown to correlate with prostate cancer cell survival (Isaacs et al, 2003;Ayala et al, 2004;Zhang and Burrows, 2004;Kleeberger et al, 2007;Mohler, 2008); so the potential of KU675 to trigger degradation of client proteins, effect on HSP modulators, and effect on HSP induction were analyzed in PC3MM2 (Fig. 4A), LNCap-LN3 (Fig.…”

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

“…[1][2][3][4][5][6][7] The genomic effects of androgens are mediated by the androgen receptor (AR), a nuclear transcription factor that mediates transcriptional responses by targeting sequence-specific DNA regulatory elements. The AR has oncogenic potential, 8 and elevated levels of this protein in clinically localized prostate cancer are predictive of disease progression after radical prostatectomy.…”