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

Abstract

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