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

Laura Cato; Jonas de Tribolet-Hardy; Irene Lee; Jaice T Rottenberg; Ilsa Coleman; Diana Melchers; René Houtman; Tengfei Xiao; Wei Li; Takuma Uo; Shihua Sun; Nane C Kuznik; Bettina Göppert; Fatma Ozgun; Martin E van Royen; Adriaan B Houtsmuller; Raga Vadhi; Prakash K Rao; Lewyn Li; Steven P Balk; Robert B Den; Bruce J Trock; R Jeffrey Karnes; Robert B Jenkins; Eric A Klein; Elai Davicioni; Friederike J Gruhl; Henry W Long; X Shirley Liu; Andrew C B Cato; Nathan A Lack; Peter S Nelson; Stephen R Plymate; Anna C Groner; Myles Brown

doi:10.1016/j.ccell.2019.01.008

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

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

Authors

Laura Cato¹, Jonas de Tribolet-Hardy², Irene Lee¹, Jaice T Rottenberg¹, Ilsa Coleman³, Diana Melchers⁴, René Houtman⁴, Tengfei Xiao⁵, Wei Li⁶, Takuma Uo⁷, Shihua Sun⁷, Nane C Kuznik⁸, Bettina Göppert⁹, Fatma Ozgun¹⁰, Martin E van Royen¹¹, Adriaan B Houtsmuller¹¹, Raga Vadhi¹, Prakash K Rao¹, Lewyn Li¹, Steven P Balk¹², Robert B Den¹³, Bruce J Trock¹⁴, R Jeffrey Karnes¹⁴, Robert B Jenkins¹⁵, Eric A Klein¹⁶, Elai Davicioni¹⁷, Friederike J Gruhl⁹, Henry W Long¹, X Shirley Liu⁶, Andrew C B Cato⁸, Nathan A Lack¹⁸, Peter S Nelson³, Stephen R Plymate¹⁹, Anna C Groner²⁰, Myles Brown²¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alternative Splicing*
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Male
Prostatic Neoplasms, Castration-Resistant / genetics*
Prostatic Neoplasms, Castration-Resistant / metabolism
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism*
Tissue Array Analysis
Transcription, Genetic

Substances

AR protein, human
Receptors, Androgen

Abstract

Publication types

MeSH terms

Substances

Grants and funding