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

Mukherjee R, McGuinness DH, McCall P, Underwood MA, Seywright M, Orange C, Edwards J - Br. J. Cancer (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: College of Medical, Veterinary and Life Sciences, Institute of Cancer, McGregor Building, Glasgow Western Infirmary, Glasgow G11 6NT, UK.

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.

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Kaplan–Meier plot for patients who showed a rise in nuclear MAPK expression with the development of CRPC compared with those who did not. There was a significant difference in (A) time to death from relapse in these patient subgroups (P=0.0255) and (B) disease-specific survival in these patient subgroups (P=0.0068).
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fig3: Kaplan–Meier plot for patients who showed a rise in nuclear MAPK expression with the development of CRPC compared with those who did not. There was a significant difference in (A) time to death from relapse in these patient subgroups (P=0.0255) and (B) disease-specific survival in these patient subgroups (P=0.0068).

Mentions: Patients whose nuclear MAPK expression rose with the development of CRPC had a significantly shorter time to death from relapse (1.40 (1.20–1.61) years) compared with samples that showed a fall or no change in expression (3.00 (1.43–4.57) years), P=0.0255 (Figure 3A). This translated into a shorter disease-specific survival of 3.37 (1.58–5.16 ) years compared with 6.89 (5.70–8.08) years, P=0.0068 (Figure 3B). Interestingly, there was also an association seen between rising cytoplasmic pMAPK (Thr202/204) expression and reduced time to biochemical relapse (P=0.06).


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

Mukherjee R, McGuinness DH, McCall P, Underwood MA, Seywright M, Orange C, Edwards J - Br. J. Cancer (2011)

Kaplan–Meier plot for patients who showed a rise in nuclear MAPK expression with the development of CRPC compared with those who did not. There was a significant difference in (A) time to death from relapse in these patient subgroups (P=0.0255) and (B) disease-specific survival in these patient subgroups (P=0.0068).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111196&req=5

fig3: Kaplan–Meier plot for patients who showed a rise in nuclear MAPK expression with the development of CRPC compared with those who did not. There was a significant difference in (A) time to death from relapse in these patient subgroups (P=0.0255) and (B) disease-specific survival in these patient subgroups (P=0.0068).
Mentions: Patients whose nuclear MAPK expression rose with the development of CRPC had a significantly shorter time to death from relapse (1.40 (1.20–1.61) years) compared with samples that showed a fall or no change in expression (3.00 (1.43–4.57) years), P=0.0255 (Figure 3A). This translated into a shorter disease-specific survival of 3.37 (1.58–5.16 ) years compared with 6.89 (5.70–8.08) years, P=0.0068 (Figure 3B). Interestingly, there was also an association seen between rising cytoplasmic pMAPK (Thr202/204) expression and reduced time to biochemical relapse (P=0.06).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: College of Medical, Veterinary and Life Sciences, Institute of Cancer, McGregor Building, Glasgow Western Infirmary, Glasgow G11 6NT, UK.

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.

Show MeSH
Related in: MedlinePlus