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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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Prostate-specific antigen correlates with Raf and MAPK in HNPC tumours. (A) PSA correlation with Raf-1 (P=0.0142, r2=0.096); (B) PSA correlation with pRaf (Ser259) (P=0.043, r2=0.0655); (C) PSA correlation with MAPK nuclear (P=0.0029, r2=0.1502); (D) PSA correlation with MAPK cytoplasmic (P<0.0001, r2=0.2467); (E) PSA correlation with pMAPK cytoplasmic (P<0.0001, r2=0.2891); and (F) PSA correlation with pMAPK nuclear (P=0.0001, r2=0.2233).
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fig6: Prostate-specific antigen correlates with Raf and MAPK in HNPC tumours. (A) PSA correlation with Raf-1 (P=0.0142, r2=0.096); (B) PSA correlation with pRaf (Ser259) (P=0.043, r2=0.0655); (C) PSA correlation with MAPK nuclear (P=0.0029, r2=0.1502); (D) PSA correlation with MAPK cytoplasmic (P<0.0001, r2=0.2467); (E) PSA correlation with pMAPK cytoplasmic (P<0.0001, r2=0.2891); and (F) PSA correlation with pMAPK nuclear (P=0.0001, r2=0.2233).

Mentions: Further downstream, activated pRaf (Ser338) in the cytoplasm strongly correlated with phosphorylated c-jun (P=0.0009, r2=0.2673) and total MAPK (cytoplasmic) correlated weakly with c-Fos (P=0.0453, r2=0.09418) (Figure 5). There were no correlations seen between MAPK and its activated form with c-jun, phospho c-Jun or c-Fos. In addition, PSA showed weak correlations with Raf-1 (P=0.0142, r2=0.09604), pRaf (Ser259) (P=0.043, r2=0.06547), and showed links to overall MAPK levels, MAPK (nuclear) (P=0.0029, r2=0.1502) and MAPK (cytoplasmic) (P<0.0001, r2=0.2467), with strong ties to the activated forms, pMAPK (Thr202/204) (cytoplasmic) (P<0.0001, r2=0.2891) and pMAPK (Thr202/204) (nuclear) (P=0.0001, r2=0.2233) (Figure 6), whereas AR showed no correlations with Raf, MAPK or any of their forms.


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)

Prostate-specific antigen correlates with Raf and MAPK in HNPC tumours. (A) PSA correlation with Raf-1 (P=0.0142, r2=0.096); (B) PSA correlation with pRaf (Ser259) (P=0.043, r2=0.0655); (C) PSA correlation with MAPK nuclear (P=0.0029, r2=0.1502); (D) PSA correlation with MAPK cytoplasmic (P<0.0001, r2=0.2467); (E) PSA correlation with pMAPK cytoplasmic (P<0.0001, r2=0.2891); and (F) PSA correlation with pMAPK nuclear (P=0.0001, r2=0.2233).
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fig6: Prostate-specific antigen correlates with Raf and MAPK in HNPC tumours. (A) PSA correlation with Raf-1 (P=0.0142, r2=0.096); (B) PSA correlation with pRaf (Ser259) (P=0.043, r2=0.0655); (C) PSA correlation with MAPK nuclear (P=0.0029, r2=0.1502); (D) PSA correlation with MAPK cytoplasmic (P<0.0001, r2=0.2467); (E) PSA correlation with pMAPK cytoplasmic (P<0.0001, r2=0.2891); and (F) PSA correlation with pMAPK nuclear (P=0.0001, r2=0.2233).
Mentions: Further downstream, activated pRaf (Ser338) in the cytoplasm strongly correlated with phosphorylated c-jun (P=0.0009, r2=0.2673) and total MAPK (cytoplasmic) correlated weakly with c-Fos (P=0.0453, r2=0.09418) (Figure 5). There were no correlations seen between MAPK and its activated form with c-jun, phospho c-Jun or c-Fos. In addition, PSA showed weak correlations with Raf-1 (P=0.0142, r2=0.09604), pRaf (Ser259) (P=0.043, r2=0.06547), and showed links to overall MAPK levels, MAPK (nuclear) (P=0.0029, r2=0.1502) and MAPK (cytoplasmic) (P<0.0001, r2=0.2467), with strong ties to the activated forms, pMAPK (Thr202/204) (cytoplasmic) (P<0.0001, r2=0.2891) and pMAPK (Thr202/204) (nuclear) (P=0.0001, r2=0.2233) (Figure 6), whereas AR showed no correlations with Raf, MAPK or any of their forms.

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