title: Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors.
abstract: BACKGROUND
  Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity.
  
  
  METHODS
  M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung.
  
  
  RESULTS
  Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells.
  
  
  CONCLUSIONS
  This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA. splymate@washington.edu
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Marie K
authors.initials: MK
authors.lastname: Tennant
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Culp
authors.forename: Lillie
authors.initials: L
authors.lastname: Woodke
authors.forename: Marco
authors.initials: M
authors.lastname: Marcelli
authors.forename: Ilsa
authors.initials: I
authors.lastname: Colman
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Julie M
authors.initials: JM
authors.lastname: Carroll
authors.forename: Charles T
authors.initials: CT
authors.lastname: Roberts
authors.forename: Joy L
authors.initials: JL
authors.lastname: Ware
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000503:physiopathology / Q000556:secondary*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D000728:Androgens; D013196:Dihydrotestosterone; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D011944:Receptors, Androgen