Androgen receptor as a target in androgen-independent prostate cancer.
Prostate cancer is dependent on androgen stimulation mediated by the androgen receptor (AR), a member of the steroid hormone receptor family of ligand-dependent nuclear receptors. Most patients respond to standard androgen ablation therapies, but virtually all patients eventually relapse with disease that has been termed hormone-refractory or androgen-independent disease. Efforts to use AR antagonists, such as flutamide or bicalutamide, to enhance responses to primary androgen ablation therapy or to treat androgen-independent prostate cancer have been disappointing, which has diminished enthusiasm for more aggressive or alternative methods to block AR function. However, many lines of evidence indicate that AR function contributes to tumor cell survival after androgen ablation and to growth of androgen-independent prostate cancer. This article outlines a number of mechanisms that may contribute to AR activity in androgen-independent prostate cancer, including AR amplification, AR mutation, altered expression of AR coactivator and corepressor proteins, and activation of other pathways that can enhance AR function. Understanding the mechanisms responsible for AR function in androgen-independent prostate cancer should allow the more rational development of antagonists that can enhance the efficacy of androgen ablation therapies.
Balk
Steven P
SP
Cancer Biology Program, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. sbalk@caregroup.harvard.edu
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D005485:Flutamide / Q000008:administration & dosage; D006801:Humans; D008297:Male; D009154:Mutation; D009570:Nitriles; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D005485:Flutamide; C053541:bicalutamide