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

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