1. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer
- Author
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Stoyanova, Tanya, Riedinger, Mireille, Lin, Shu, Faltermeier, Claire M, Smith, Bryan A, Zhang, Kelvin X, Going, Catherine C, Goldstein, Andrew S, Lee, John K, Drake, Justin M, Rice, Meghan A, Hsu, En-Chi, Nowroozizadeh, Behdokht, Castor, Brandon, Orellana, Sandra Y, Blum, Steven M, Cheng, Donghui, Pienta, Kenneth J, Reiter, Robert E, Pitteri, Sharon J, Huang, Jiaoti, and Witte, Owen N
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Prostate Cancer ,Cancer ,Aging ,Amyloid Precursor Protein Secretases ,Animals ,Biomarkers ,Cell Line ,Tumor ,Cell Nucleus ,Disease Models ,Animal ,Disease Progression ,Epithelial-Mesenchymal Transition ,Gene Expression ,Gene Expression Profiling ,Heterografts ,Humans ,Immunohistochemistry ,Male ,Mice ,Mitogen-Activated Protein Kinases ,Neoplasm Grading ,Neoplasm Metastasis ,Phenotype ,Prostatic Neoplasms ,Castration-Resistant ,Proto-Oncogene Proteins c-akt ,Proto-Oncogene Proteins c-myc ,Receptor ,Notch1 ,Signal Transduction ,Tumor Burden ,raf Kinases ,ras Proteins ,prostate ,cancer ,Notch1 - Abstract
Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.
- Published
- 2016