1. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells
- Author
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Lee, JK, Phillips, JW, Smith, BA, Park, JW, Stoyanova, T, McCaffrey, EF, Baertsch, R, Sokolov, A, Meyerowitz, JG, Mathis, C, Cheng, D, Stuart, JM, Shokat, KM, Gustafson, WC, Huang, J, and Witte, ON
- Subjects
Male ,Aging ,Cell Transformation ,Mice ,2.1 Biological and endogenous factors ,Exome ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Aetiology ,Aurora Kinase A ,Cancer ,Tumor ,Prostate Cancer ,Azepines ,myc ,Neoplasm Proteins ,Neuroendocrine Tumors ,5.1 Pharmaceuticals ,Neoplastic Stem Cells ,Development of treatments and therapeutic interventions ,Biotechnology ,Urologic Diseases ,Recombinant Fusion Proteins ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Laser Capture Microdissection ,Adenocarcinoma ,SCID ,Cell Line ,Proto-Oncogene Proteins c-myc ,Transduction ,Genetic ,Animals ,Humans ,Neoplasm Invasiveness ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,Neoplastic ,Phenylurea Compounds ,Neurosciences ,Prostatic Neoplasms ,Epithelial Cells ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Pyrimidines ,Gene Expression Regulation ,Genes ,Inbred NOD ,Orchiectomy ,Proto-Oncogene Proteins c-akt - Abstract
© 2016 Elsevier Inc. MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.
- Published
- 2016
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