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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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Raf and MAPK localisation in prostate cancer. Tissue sections counterstained with haematoxylin showing (magnification × 400) (A) total Raf; (B) inactive pRaf (Ser259); (C) active pRaf (Ser338); (D) total MAPK; and (E) activated (phospho) MAPK localisations in prostate cancer. Inset shows higher magnification images.
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fig1: Raf and MAPK localisation in prostate cancer. Tissue sections counterstained with haematoxylin showing (magnification × 400) (A) total Raf; (B) inactive pRaf (Ser259); (C) active pRaf (Ser338); (D) total MAPK; and (E) activated (phospho) MAPK localisations in prostate cancer. Inset shows higher magnification images.

Mentions: Raf-1 was observed in the cytoplasm and peri-membrane areas (Figure 1A), and the inactive form of Raf-1 was found only in the peri-membrane region (Figure 1B); however, the activated form of Raf-1 was observed in the cytoplasm, nucleus and the cell membrane (Figure 1C). Mitogen-activated protein kinase and phosphorylated MAPK (pMAPK) (Thr202/204) were observed in the nucleus and cytoplasm (Figure 1D).


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)

Raf and MAPK localisation in prostate cancer. Tissue sections counterstained with haematoxylin showing (magnification × 400) (A) total Raf; (B) inactive pRaf (Ser259); (C) active pRaf (Ser338); (D) total MAPK; and (E) activated (phospho) MAPK localisations in prostate cancer. Inset shows higher magnification images.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Raf and MAPK localisation in prostate cancer. Tissue sections counterstained with haematoxylin showing (magnification × 400) (A) total Raf; (B) inactive pRaf (Ser259); (C) active pRaf (Ser338); (D) total MAPK; and (E) activated (phospho) MAPK localisations in prostate cancer. Inset shows higher magnification images.
Mentions: Raf-1 was observed in the cytoplasm and peri-membrane areas (Figure 1A), and the inactive form of Raf-1 was found only in the peri-membrane region (Figure 1B); however, the activated form of Raf-1 was observed in the cytoplasm, nucleus and the cell membrane (Figure 1C). Mitogen-activated protein kinase and phosphorylated MAPK (pMAPK) (Thr202/204) were observed in the nucleus and cytoplasm (Figure 1D).

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