Abstract
To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Disease Models, Animal
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Disease Progression
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Enzyme Activation
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Epidermal Growth Factor / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / genetics
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Homeodomain Proteins / genetics
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MAP Kinase Signaling System
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Male
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Mice
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Mice, Mutant Strains
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Neoplasm Recurrence, Local / genetics
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / pathology
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Oncogene Protein p65(gag-jun) / biosynthesis
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Oncogene Protein p65(gag-jun) / genetics*
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Oncogene Protein p65(gag-jun) / metabolism
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PTEN Phosphohydrolase / genetics
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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Proto-Oncogene Proteins c-fos / biosynthesis
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Proto-Oncogene Proteins c-fos / genetics*
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Proto-Oncogene Proteins c-fos / metabolism
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Transcription Factor AP-1 / biosynthesis
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Transcription Factor AP-1 / genetics*
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Transcription Factor AP-1 / metabolism
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Transcription Factors / genetics
Substances
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Homeodomain Proteins
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Nkx3-1 protein, mouse
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Oncogene Protein p65(gag-jun)
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Proto-Oncogene Proteins c-fos
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Transcription Factor AP-1
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Transcription Factors
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Epidermal Growth Factor
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Mitogen-Activated Protein Kinase Kinases
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PTEN Phosphohydrolase
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Pten protein, mouse