ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients
- Esther Baena1,2,
- Zhen Shao1,2,3,9,
- Douglas E. Linn4,9,
- Kimberly Glass3,
- Melanie J. Hamblen1,2,5,
- Yuko Fujiwara1,2,5,
- Jonghwan Kim1,2,
- Minh Nguyen1,2,
- Xin Zhang4,
- Frank J. Godinho1,2,5,
- Roderick T. Bronson6,
- Lorelei A. Mucci7,
- Massimo Loda8,
- Guo-Cheng Yuan3,
- Stuart H. Orkin1,2,5,10 and
- Zhe Li1,2,4,10
- 1Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
- 2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02115, USA;
- 4Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
- 5Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
- 6Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 7Department of Epidemiology, Harvard School of Public Health, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
- 8Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
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↵9 These authors contributed equally to this work.
Abstract
Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.
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Footnotes
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↵10 Corresponding authors
E-mail stuart_orkin{at}dfci.harvard.edu
E-mail zli4{at}rics.bwh.harvard.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.211011.112.
- Received November 27, 2012.
- Accepted February 20, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.