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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.
Highlights
Recent advances in detection and treatment of organ-confined prostate cancer have significantly improved the prognosis for men with the disease
We focused on the dorsolateral lobe of the mouse prostate, as it is generally considered to be most analogous to the peripheral zone of the human prostate
There is mounting evidence demonstrating the value of interrogating mouse models of cancer to gain molecular insights into the mechanisms of human cancer
Summary
Recent advances in detection and treatment of organ-confined prostate cancer have significantly improved the prognosis for men with the disease. Prostate tumors vary in their degree of aggressiveness: Whereas many are fairly indolent and readily curable by surgery or radiation therapy, some are more aggressive and have less favorable outcomes. Current modalities for distinguishing indolent from aggressive forms of the disease are largely reliant on the clinical behavior and/or morphologic features. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Abate-Shen: Department of Urology, Columbia University, College of Physicians and Surgeons, Herbert Irving Cancer Center, New York, NY 10032. Al-Ahmadie: Department of Pathology, University of Chicago Medical Center, Chicago, IL 60637
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