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Cancer Cell. 2016 Oct 10;30(4):563-577. doi: 10.1016/j.ccell.2016.09.005.

N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer.

Author information

1
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
2
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
3
Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
4
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA; Tri-Institutional Training Program in Computational Biology and Medicine of Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, and Cornell University, Ithaca, NY 14853, USA.
5
Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
6
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA; Tri-Institutional Training Program in Computational Biology and Medicine of Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, and Cornell University, Ithaca, NY 14853, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
10
Theodor Boveri Institute and Comprehensive Cancer Center Mainfranken, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
11
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA.
12
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065 USA.
13
Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
14
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: dsr2005@med.cornell.edu.

Abstract

The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

KEYWORDS:

Aurora kinase A; EZH2; N-Myc; castration-resistant prostate adenocarcinoma; genetically engineered mouse; neuroendocrine prostate cancer; prostate cancer organoid

PMID:
27728805
PMCID:
PMC5540451
DOI:
10.1016/j.ccell.2016.09.005
[Indexed for MEDLINE]
Free PMC Article

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