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Activator Protein-1 Transcription Factors Are Associated with Progression and Recurrence of Prostate Cancer

¹ Center for Advanced Biotechnology and Medicine, Departments of ² Medicine, ³ Pediatrics, and ⁴ Biometrics, ⁵ The Cancer Institute of New Jersey, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey; ⁶ Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; Departments of ⁷ Pathology, ⁸ Surgery (Urology), ⁹ Human Oncology and Pathogenesis, and ¹⁰ Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York

Requests for reprints: Cory Abate-Shen, Department of Urology, Columbia University, College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, Room 217A, New York, NY 10032. Phone: 212-851-4731; Fax: 212-851-4572; E-mail: cabateshen{at}columbia.edu.

Key Words: AP-1 • mouse models • prostate cancer

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. [Cancer Res 2008;68(7):2132–44]

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