title: Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer.
abstract: BACKGROUND
  Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC.
  
  
  METHODS
  Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway.
  
  
  RESULTS
  Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours.
  
  
  CONCLUSIONS
  We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer.
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Cancer, McGregor Building, Glasgow Western Infirmary, Glasgow G11 6NT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.forename: D H
authors.initials: DH
authors.lastname: McGuinness
authors.forename: P
authors.initials: P
authors.lastname: McCall
authors.forename: M A
authors.initials: MA
authors.lastname: Underwood
authors.forename: M
authors.initials: M
authors.lastname: Seywright
authors.forename: C
authors.initials: C
authors.lastname: Orange
authors.forename: J
authors.initials: J
authors.lastname: Edwards
mesh_terms: D000368:Aged; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology
chemical_list: D020928:Mitogen-Activated Protein Kinases; D017430:Prostate-Specific Antigen; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human