GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance

Abstract
Data availability
Article and author information
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Abstract

Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.

Data availability

RNA-seq data has been deposited in GEO under accession code GSE120720. ChIP-seq data has been deposited in GEO under accession code GSE120680

The following data sets were generated

1. Lee E
2. Wongvipat J
3. Choi D
4. Wang P
5. Lee YS
6. Zheng D
7. Watson PA
8. Gopalan A
9. Sawyers CL
(2018) GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance
NCBI Gene Expression Omnibus, GSE120720.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120720
1. Lee E
2. Wongvipat J
3. Choi D
4. Wang P
5. Lee YS
6. Zheng D
7. Watson PA
8. Gopalan A
9. Sawyers CL
(2018) GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance
NCBI Gene Expression Omnibus, GSE120680.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120680

The following previously published data sets were used

1. Robinson D et al
(2015) Integrative clinical genomics of advanced prostate cancer
NCBI dbGap, phs000915.v1.p1.

https://www.ncbi.nlm.nih.gov/gap/?term=phs000915.v1.p1
1. Cancer Genome Atlas Research Network
(2015) The Molecular Taxonomy of Primary Prostate Cancer
cBioPortal for Cancer Genomics.

http://www.cbioportal.org/study.do?cancer_study_id=prad_tcga_pub

Article and author information

Author details

Eugine Lee

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
No competing interests declared.
John Wongvipat

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
John Wongvipat, co-inventor of enzalutamide.
Danielle Choi

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
No competing interests declared.
Ping Wang

Department of Genetics, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.
Young Sun Lee

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
No competing interests declared.
Deyou Zheng

Department of Genetics, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-4354-5337
Philip A Watson

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
No competing interests declared.
Anuradha Gopalan

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
No competing interests declared.
Charles L Sawyers

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

For correspondence
sawyersc@mskcc.org

Competing interests
Charles L Sawyers, Senior editor, eLife; Board of Directors of Novartis; co-founder of ORIC Pharm; co-inventor of enzalutamide and apalutamide; Science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV; co-founder of Seragon, purchased by Genentech/Roche in 2014.

"This ORCID iD identifies the author of this article:" 0000-0003-4955-6475

Funding

Howard Hughes Medical Institute

Charles L Sawyers

National Institutes of Health (CA008748)

Charles L Sawyers

National Institutes of Health (CA155169)

Charles L Sawyers

U.S. Department of Defense (W81XWH-15-1-0540)

Eugine Lee

Starr Cancer Consortium (I10-0062)

Charles L Sawyers

Iris & Junming Le Foundation

Eugine Lee

National Institutes of Health (CA193837)

Charles L Sawyers

National Institutes of Health (CA224079)

Charles L Sawyers

National Institutes of Health (CA092629)

Charles L Sawyers

National Institutes of Health (CA160001)

Charles L Sawyers

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 in compliance with the approved institutional animal care and use committee (IACUC) protocols (#06-07-012) of the Research Animal Resource Center of Memorial Sloan Kettering Cancer Center.

Copyright

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.