prostate-organoid-cultures-as-tools-to-translate-genotypes-mutational

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

Presented here is a protocol to study pharmacodynamics, stem cell potential, and cancer differentiation in prostate epithelial organoids. Prostate ...

Memorial Sloan Kettering Cancer Center

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.

Danielle Choi

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JoVE Journal Publications

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