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

Tanya Stoyanova; Mireille Riedinger; Shu Lin; Claire M Faltermeier; Bryan A Smith; Kelvin X Zhang; Catherine C Going; Andrew S Goldstein; John K Lee; Justin M Drake; Meghan A Rice; En-Chi Hsu; Behdokht Nowroozizadeh; Brandon Castor; Sandra Y Orellana; Steven M Blum; Donghui Cheng; Kenneth J Pienta; Robert E Reiter; Sharon J Pitteri; Jiaoti Huang; Owen N Witte

doi:10.1073/pnas.1614529113

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. Epub 2016 Sep 30.

Authors

Tanya Stoyanova¹, Mireille Riedinger², Shu Lin³, Claire M Faltermeier⁴, Bryan A Smith⁴, Kelvin X Zhang⁵, Catherine C Going⁶, Andrew S Goldstein⁷, John K Lee⁸, Justin M Drake⁹, Meghan A Rice⁶, En-Chi Hsu⁶, Behdokht Nowroozizadeh¹⁰, Brandon Castor¹¹, Sandra Y Orellana⁴, Steven M Blum¹², Donghui Cheng¹³, Kenneth J Pienta¹⁴, Robert E Reiter³, Sharon J Pitteri⁶, Jiaoti Huang¹⁵, Owen N Witte¹⁶

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; stanya@stanford.edu owenwitte@mednet.ucla.edu.
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 stanya@stanford.edu owenwitte@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors
Animals
Biomarkers
Cell Line, Tumor
Cell Nucleus / metabolism
Disease Models, Animal
Disease Progression
Epithelial-Mesenchymal Transition / genetics
Gene Expression
Gene Expression Profiling
Heterografts
Humans
Immunohistochemistry
Male
Mice
Mitogen-Activated Protein Kinases
Neoplasm Grading
Neoplasm Metastasis
Phenotype
Prostatic Neoplasms, Castration-Resistant / genetics
Prostatic Neoplasms, Castration-Resistant / metabolism*
Prostatic Neoplasms, Castration-Resistant / pathology
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-myc / metabolism
Receptor, Notch1 / antagonists & inhibitors
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism*
Signal Transduction*
Tumor Burden
raf Kinases / metabolism
ras Proteins / metabolism

Substances

Biomarkers
Proto-Oncogene Proteins c-myc
Receptor, Notch1
Proto-Oncogene Proteins c-akt
raf Kinases
Mitogen-Activated Protein Kinases
Amyloid Precursor Protein Secretases
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding