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Cancer Cell. 2019 Mar 18;35(3):401-413.e6. doi: 10.1016/j.ccell.2019.01.008. Epub 2019 Feb 14.

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
3
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4
PamGene International B.V., 5211 HH Den Bosch, the Netherlands.
5
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, MA 02215, USA.
6
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, MA 02215, USA.
7
Department of Medicine, University of Washington School of Medicine and GRECC-VAPSHCS, Seattle, WA 98104, USA.
8
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
9
Institute of Microstructure Technology, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
10
School of Medicine, Koç University, 34450 Istanbul, Turkey.
11
Department of Pathology, Erasmus Optical Imaging Centre, Erasmus MC, 3015 GE Rotterdam, the Netherlands.
12
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
13
Department of Radiation Oncology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA.
14
Department of Urology, Mayo Clinic, Rochester, MN 55905, USA.
15
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
16
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
17
GenomeDx Inc., San Diego, CA 92121, USA.
18
School of Medicine, Koç University, 34450 Istanbul, Turkey; Vancouver Prostate Center, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
19
Department of Medicine, University of Washington School of Medicine and GRECC-VAPSHCS, Seattle, WA 98104, USA. Electronic address: splymate@u.washington.edu.
20
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland. Electronic address: anna.groner@hotmail.com.
21
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: myles_brown@dfci.harvard.edu.

Abstract

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7.

KEYWORDS:

AR variant v7 (ARv7); androgen receptor (AR); castration-resistant prostate cancer (CRPC); transcription

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