title: Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours.
abstract: Several options for the endocrine treatment of non-organ-confined prostate cancer are available. They include surgical or medical removal of androgenic hormones or administration of non-steroidal anti-androgens. However, tumour progression after a period of remission of the disease inevitably occurs in virtually all patients. The androgen receptor (AR) is, in various tumour models, implicated in the development of therapy resistance but molecular mechanisms that by-pass the receptor have also been described. Adaptation mechanisms relevant to tumour recurrence include up-regulation of AR mRNA and protein, overexpression of AR coactivators, increased activation of mutated receptors by steroids and anti-androgens, and ligand-independent activation. For research studies, sublines that respond to but do not depend on androgen for their proliferation were generated. Coactivators SRC-1, TIF-2, RAC3, p300, CBP, Tip60, and gelsolin are highly expressed in endocrine therapy-resistant prostate cancer. AR point mutations are increasingly detected in relapsed cancers and contribute to the failure of endocrine therapy in a subgroup of patients. Ligand-independent activation of the AR by HER-2/neu and interleukin-6 is associated with activation of the signalling pathway of mitogen-activated protein kinase. Increased activity of intracellular kinases may affect cellular events in both an AR-dependent and -independent manner. Mitogen-activated protein kinases are strongly phosphorylated in endocrine therapy-resistant prostate tumours. Similarly, activation of the AR by phosphorylated protein kinase B, Akt, has also been reported in prostate cancer. Activation of the Akt pathway contributes to increased survival of prostate tumour cells.
authors.affiliation: Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. zoran.culig@uibk.ac.at
authors.forename: Z
authors.initials: Z
authors.lastname: Culig
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.forename: G
authors.initials: G
authors.lastname: Bartsch
authors.forename: A
authors.initials: A
authors.lastname: Hobisch
mesh_terms: D000728:Androgens / Q000627:therapeutic use*; D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D017211:Treatment Failure
chemical_list: D000728:Androgens; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases