title: N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stoyanova
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Erin F
authors.initials: EF
authors.lastname: McCaffrey
authors.affiliation: Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Baertsch
authors.affiliation: Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Artem
authors.initials: A
authors.lastname: Sokolov
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Meyerowitz
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Donghui
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: W Clay
authors.initials: WC
authors.lastname: Gustafson
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Immunology, and Medical Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: owenwitte@mednet.ucla.edu.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000502:physiology; D001381:Azepines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D009919:Orchiectomy; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C000592902:CD532 compound; C550258:MLN 8237; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C494918:AKT1 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt