2. Academic Validation
  3. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

  • Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6457-E6466. doi: 10.1073/pnas.1614529113.
Tanya Stoyanova 1,  Mireille Riedinger 2,  Shu Lin 3,  Claire M Faltermeier 4,  Bryan A Smith 4,  Kelvin X Zhang 5,  Catherine C Going 6,  Andrew S Goldstein 7,  John K Lee 8,  Justin M Drake 9,  Meghan A Rice 6,  En-Chi Hsu 6,  Behdokht Nowroozizadeh 10,  Brandon Castor 11,  Sandra Y Orellana 4,  Steven M Blum 12,  Donghui Cheng 13,  Kenneth J Pienta 14,  Robert E Reiter 3,  Sharon J Pitteri 6,  Jiaoti Huang 15,  Owen N Witte 16
Affiliations

Affiliations

  • 1 Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; [email protected] [email protected].
  • 2 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
  • 3 Department of Urology, University of California, Los Angeles, CA 90095.
  • 4 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
  • 5 Department of Biological Chemistry, University of California, Los Angeles, CA 90095.
  • 6 Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304.
  • 7 Department of Urology, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095.
  • 8 Division of Hematology and Medical Oncology, University of California, Los Angeles, CA 90095.
  • 9 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903; Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901.
  • 10 Department of Pathology, University of California, Irvine, CA 92697; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
  • 11 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
  • 12 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA 02115.
  • 13 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
  • 14 Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287.
  • 15 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095; Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
  • 16 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 [email protected] [email protected].
PMID: 27694579 DOI: 10.1073/pnas.1614529113
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.

Keywords

Notch1; cancer; prostate.

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