1. Cancer Biology
  2. Developmental Biology and Stem Cells
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Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

  1. Chee Wai Chua
  2. Nusrat J Epsi
  3. Eva Y Leung
  4. Shouhong Xuan
  5. Ming Lei
  6. Bo I Li
  7. Sarah K Bergren
  8. Hanina Hibshoosh
  9. Antonina Mitrofanova
  10. Michael M Shen  Is a corresponding author
  1. Columbia University Medical Center, United States
  2. Rutgers, The State University of New Jersey, United States
Research Article
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Cite as: eLife 2018;7:e28768 doi: 10.7554/eLife.28768

Abstract

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor that functions in prostate regeneration. Using genetically-engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras results in AR-negative tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.

Article and author information

Author details

  1. Chee Wai Chua

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nusrat J Epsi

    Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-5363-075X
  3. Eva Y Leung

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shouhong Xuan

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ming Lei

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Bo I Li

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah K Bergren

    Department of Medicine, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hanina Hibshoosh

    Department of Pathology and Cell Biology, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Antonina Mitrofanova

    Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael M Shen

    Department of Medicine, Columbia University Medical Center, New York, United States
    For correspondence
    mshen@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-4042-1657

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (DK076602)

  • Michael M Shen

National Cancer Institute (CA1966692)

  • Michael M Shen

U.S. Department of Defense (Prostate Cancer Research Program PC101820)

  • Chee Wai Chua

U.S. Department of Defense (Prostate Cancer Research Program PC141064)

  • Bo I Li

Prostate Cancer Foundation

  • Michael M Shen

Rutgers SHP Dean's Intramural Grant

  • Antonina Mitrofanova

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed under protocol AAAR9408, which was approved by the Institutional Animal Care and Use Committee at Columbia University Medical Center.

Human subjects: Radical prostatectomy samples were obtained from consented patients under the auspices of an Institutional Review Board approved protocol AAAC4997 at Columbia University Medical Center.

Reviewing Editor

  1. Sean J Morrison, Reviewing Editor, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: May 18, 2017
  2. Accepted: January 12, 2018
  3. Accepted Manuscript published: January 15, 2018 (version 1)
  4. Version of Record published: February 9, 2018 (version 2)
  5. Version of Record updated: February 15, 2018 (version 3)

Copyright

© 2018, Chua et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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