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

Mukherjee, R., Mcguinness, D.H. , McCall, P., Underwood, M. A., Seywright, M., Orange, C. and Edwards, J. (2011) Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer. British Journal of Cancer, 104(12), pp. 1920-1928. (doi: 10.1038/bjc.2011.163) (PMID:21559022) (PMCID:PMC3111196)

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. 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. British Journal of Cancer (2011) 104, 1920-1928. doi:10.1038/bjc.2011.163 www.bjcancer.com Published online 10 May 2011 (C) 2011 Cancer Research UK

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Edwards, Professor Joanne and McCall, Dr Pamela and Mcguinness, Dr David
• Authors: Mukherjee, R., Mcguinness, D.H., McCall, P., Underwood, M. A., Seywright, M., Orange, C., and Edwards, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: British Journal of Cancer
• ISSN: 0007-0920