Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation
- Columbia University Medical Center, United States
- Rutgers, The State University of New Jersey, United States
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.
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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.
Reviewing Editor
- Sean J Morrison, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
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.
Version history
- Received: May 18, 2017
- Accepted: January 12, 2018
- Accepted Manuscript published: January 15, 2018 (version 1)
- Version of Record published: February 9, 2018 (version 2)
- 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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Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation
eLife 7:e28768.
https://doi.org/10.7554/eLife.28768
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