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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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Activated Raf correlates with Her2 and activated Her2 (pHer2) in CRPC tumours. (A) Her2 correlation with pRaf (Ser338) cytoplasmic (P=0.0035, r2=0.1854); (B) Her2 correlation with pRaf (Ser338) nuclear (P=0.0068, r2=0.1581); (C) pHer2 correlation with pRaf (Ser259) (P=0.0008, r2=0.2011); and (D) pHer2 correlation with pRaf (Ser338) cytoplasmic (P=0.0363, r2=0.0938).
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fig7: Activated Raf correlates with Her2 and activated Her2 (pHer2) in CRPC tumours. (A) Her2 correlation with pRaf (Ser338) cytoplasmic (P=0.0035, r2=0.1854); (B) Her2 correlation with pRaf (Ser338) nuclear (P=0.0068, r2=0.1581); (C) pHer2 correlation with pRaf (Ser259) (P=0.0008, r2=0.2011); and (D) pHer2 correlation with pRaf (Ser338) cytoplasmic (P=0.0363, r2=0.0938).

Mentions: After the development of CRPC, Her2 no longer showed a correlation with Raf-1 nor a negative association became evident between pRaf (Ser338) both in the cytoplasm (P=0.0035, r2=0.1854) and nucleus (P=0.0068, r2=0.1581) with Her2. In addition, the activated form (pHer2) correlated with pRaf (Ser259) (P=0.0008, r2=0.2011). Interestingly, the activated cytoplasmic form of Raf showed a positive weak correlation with the pHer2 (P=0.0363, r2=0.09376) (Figure 7). Furthermore, no correlations were evident between Her2 or pHer2 with MAPK in any form. All associations between EGFR and EGFR vIII disappeared after progression to CRPC.


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)

Activated Raf correlates with Her2 and activated Her2 (pHer2) in CRPC tumours. (A) Her2 correlation with pRaf (Ser338) cytoplasmic (P=0.0035, r2=0.1854); (B) Her2 correlation with pRaf (Ser338) nuclear (P=0.0068, r2=0.1581); (C) pHer2 correlation with pRaf (Ser259) (P=0.0008, r2=0.2011); and (D) pHer2 correlation with pRaf (Ser338) cytoplasmic (P=0.0363, r2=0.0938).
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Related In: Results  -  Collection

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fig7: Activated Raf correlates with Her2 and activated Her2 (pHer2) in CRPC tumours. (A) Her2 correlation with pRaf (Ser338) cytoplasmic (P=0.0035, r2=0.1854); (B) Her2 correlation with pRaf (Ser338) nuclear (P=0.0068, r2=0.1581); (C) pHer2 correlation with pRaf (Ser259) (P=0.0008, r2=0.2011); and (D) pHer2 correlation with pRaf (Ser338) cytoplasmic (P=0.0363, r2=0.0938).
Mentions: After the development of CRPC, Her2 no longer showed a correlation with Raf-1 nor a negative association became evident between pRaf (Ser338) both in the cytoplasm (P=0.0035, r2=0.1854) and nucleus (P=0.0068, r2=0.1581) with Her2. In addition, the activated form (pHer2) correlated with pRaf (Ser259) (P=0.0008, r2=0.2011). Interestingly, the activated cytoplasmic form of Raf showed a positive weak correlation with the pHer2 (P=0.0363, r2=0.09376) (Figure 7). Furthermore, no correlations were evident between Her2 or pHer2 with MAPK in any form. All associations between EGFR and EGFR vIII disappeared after progression to CRPC.

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