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

   

Authors:	Lee, E.; Wongvipat, J.; Choi, D.; Wang, P.; Lee, Y. S.; Zheng, D.; Watson, P. A.; Gopalan, A.; Sawyers, C. L.
Article Title:	GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
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. © 2019, Lee et al.
Keywords:	cancer biology; enzalutamide; human; ar coactivator; ar signaling output; greb1; intra-tumoral heterogeneity
Journal Title:	eLife
Volume:	8
ISSN:	2050-084X
Publisher:	eLife Sciences Publications Ltd.
Date Published:	2019-01-15
Start Page:	e41913
Language:	English
DOI:	10.7554/eLife.41913
PUBMED:	30644358
PROVIDER:	scopus
PMCID:	PMC6336405
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060142403&doi=10.7554%2feLife.41913&partnerID=40&md5=18f99dca6f1101510fb427c1611730c6
Notes:	Article -- Export Date: 1 February 2019 -- Source: Scopus

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