Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer.
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.
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; stanya@stanford.edu owenwitte@mednet.ucla.edu.
Tanya
T
Stoyanova
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
Mireille
M
Riedinger
Department of Urology, University of California, Los Angeles, CA 90095.
Shu
S
Lin
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Claire M
CM
Faltermeier
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Bryan A
BA
Smith
Department of Biological Chemistry, University of California, Los Angeles, CA 90095.
Kelvin X
KX
Zhang
Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304.
Catherine C
CC
Going
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.
Andrew S
AS
Goldstein
Division of Hematology and Medical Oncology, University of California, Los Angeles, CA 90095.
John K
JK
Lee
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.
Justin M
JM
Drake
Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304.
Meghan A
MA
Rice
Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304.
En-Chi
EC
Hsu
Department of Pathology, University of California, Irvine, CA 92697; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
Behdokht
B
Nowroozizadeh
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
Brandon
B
Castor
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
Sandra Y
SY
Orellana
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.
Steven M
SM
Blum
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
Donghui
D
Cheng
Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287.
Kenneth J
KJ
Pienta
Department of Urology, University of California, Los Angeles, CA 90095.
Robert E
RE
Reiter
Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304.
Sharon J
SJ
Pitteri
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095; Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
Jiaoti
J
Huang
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 stanya@stanford.edu owenwitte@mednet.ucla.edu.
Owen N
ON
Witte
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D015415:Biomarkers; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D018631:ras Proteins
Notch1; cancer; prostate
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