Steroid hormone receptors (SHR) play a major role in the normal breast development and breast cancer progression. Estrogen receptor (ER) is expressed in approximately 75% of breast cancers, and the majority of these tumours also express the androgen receptor (AR). While ER-directed therapies have been effective in the majority of patients, a significant subset develops resistance and requires alternative treatment approaches. In the endocrine-resistant setting, emerging insights into the role of androgen signalling have revived interest in AR-targeted therapies for novel pre-clinical studies and clinical trials. An understanding of AR activation in this setting is critical to improve the rational design of trials involving AR-directed therapies. In this study, we sought to characterize the AR downstream signalling pathway and assess the efficacy of AR-targeted agents in endocrine-resistant cell lines and patient-derived xenografts (PDXs) models. We performed RNA-Seq and ChIP-Seq analyses to interrogate the SHR dynamic at the genomic, transcriptomic and proteomic levels. Transcriptional profiling of AR-targeted tumours revealed gene signatures (~200 genes) associated with ER-regulated genes repertoire that predicts for better disease outcome (pval=6e-10) in ER-positive breast cancer patients across METABRIC and ROCK public cohorts. AR agonists DHT and enobosarm (selective AR modulator) inhibited in vitro and in vitro tumour growth of endocrine-resistant MCF7 cells and two PDXs (Gar15-13 and HCI005) and demonstrated anti-proliferative (Hallmarks of G2M-checkpoint and E2F-targets) and anti-estrogenic (ER-targets) effects. These findings validate the utility of AR agonists in the treatment of endocrine-resistant ER-positive breast cancer, and further support the identification of biomarkers for novel AR-directed therapies and subsequent clinical trials.
17 Mar 2019 - 20 Mar 2019