Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer

Br J Cancer. 2011 Jun 7;104(12):1920-8. doi: 10.1038/bjc.2011.163. Epub 2011 May 10.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mitogen-Activated Protein Kinases / analysis
  • Orchiectomy
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms / mortality*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Proto-Oncogene Proteins c-raf / analysis
  • Proto-Oncogene Proteins c-raf / physiology
  • Receptor, ErbB-2 / physiology


  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • Prostate-Specific Antigen