RGD Reference Report - Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. - Rat Genome Database

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Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer.

Authors: McCracken, SR  Ramsay, A  Heer, R  Mathers, ME  Jenkins, BL  Edwards, J  Robson, CN  Marquez, R  Cohen, P  Leung, HY 
Citation: McCracken SR, etal., Oncogene. 2008 May 8;27(21):2978-88. Epub 2007 Dec 10.
RGD ID: 2298796
Pubmed: PMID:18071319   (View Abstract at PubMed)
DOI: DOI:10.1038/sj.onc.1210963   (Journal Full-text)

Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P<0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P<0.0001), bony metastases (P=0.0044) and locally advanced disease at diagnosis (P=0.0023), with a weak association with shorter disease-specific survival (P=0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor disease-specific survival and, on multivariant analysis, was an independent prognostic factor (P<0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n=26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P<0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm(3), in vivo (P<0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
prostate cancer  IEP 2298796 RGD 
prostate cancer  ISOMAPK7 (Homo sapiens)2298796; 2298796 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mapk7  (mitogen-activated protein kinase 7)

Genes (Mus musculus)
Mapk7  (mitogen-activated protein kinase 7)

Genes (Homo sapiens)
MAPK7  (mitogen-activated protein kinase 7)


Additional Information