Current thoughts on the role of the androgen receptor and prostate cancer progression.
Androgens play a central role in the development and maintenance of prostate tissue. Treatment of prostate cancer by androgen ablation either surgically or biochemically results in massive cell death and tumor regression. However, this is often followed by the onset of aggressive disease, which is fatal. Various studies have been conducted to understand the mechanism leading to the establishment of aggressive disease following treatment. An interesting comprehensive study recently conducted by Chen et al shows the increase in androgen receptor (AR) transcript to be the key factor in disease recurrence following treatment. This up-regulation in the AR levels is shown to increase sensitivity to low levels of androgen, leading to ligand-dependent downstream gene expression and tumor recurrence. A "mass action" model has been proposed to explain this phenomenon. Moreover, the increase in mRNA levels has been shown to facilitate conversion of classic antagonists to agonists of hormones action by the recruitment of a subset of co-activators to the promoters of AR-responsive genes. This study underscores the importance of ARs in the establishment of prostate cancer and offers several insights into the mechanism by which tumors recur following androgen ablation. The study also prompts several questions about the reason behind the observed up-regulation and also the mechanism by which classic antagonists are rendered agonistic. The need for the design of novel therapeutic analogues is also emphasized.
Setlur
Sunita R
SR
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Rubin
Mark A
MA
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000728:Androgens / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology; D011467:Prostate / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000728:Androgens; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011944:Receptors, Androgen