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Elife. 2019 Jan 15;8. pii: e41913. doi: 10.7554/eLife.41913.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States.
2
Department of Genetics, Albert Einstein College of Medicine, New York, United States.
3
Department of Neurology, Albert Einstein College of Medicine, New York, United States.
4
Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States.
6
Howard Hughes Medical Institute, Chevy Chase, United States.

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.

KEYWORDS:

AR coactivator; AR signaling output; GREB1; cancer biology; enzalutamide; human; intra-tumoral heterogeneity

Conflict of interest statement

EL, DC, PW, YL, DZ, PW, AG No competing interests declared, JW co-inventor of enzalutamide, CS 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.

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