PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Introduction: Resistance to endocrine therapy is a major clinical problem in estrogen receptor positive (ER+) breast cancer. The androgen receptor (AR) is expressed in ~90% of all primary ER+ breast cancers and high expression of AR is associated with a better patient outcome in this tumours. However, uncertainty surrounding the role of AR in endocrine resistance is reflected in current clinical trials in which both AR agonists and antagonists are being investigated. Here, we sought to investigate the optimal approach in targeting AR in endocrine-resistant breast cancer.
Methods: The consequences of AR activation, using AR cognate ligand 5α-dihydrotestosterone (DHT) and selective AR modulator enobosarm, or AR antagonism using enzalutamide were evaluated on preclinical models of endocrine-resistance.
Results: Treatment with DHT and enobosarm inhibited the growth of MCF7 TamR and LTED cells but enzalutamide had no effect. AR activation was associated with attenuation of ER signaling in both models. DHT strongly inhibited the proliferation of endocrine-resistant PDX models. Enobosarm similarly suppressed the proliferation of HCI-005 PDX, and to a lesser extent in Gar15-13 PDX. Antagonizing AR with enzalutamide had no effect on growth of Gar15-13, consistent with our in vitro data. AR agonists reduced expression levels of ER and PR in HCI-005, and transcriptomic analysis of AR agonist-treated Gar15-13 identified significant negative enrichment of genes related to proliferation and estrogen response. These observations indicate that the growth-suppressive effects of AR activation in vivo were mediated through inhibition of ER signaling. Furthermore, we established a highly prognostic AR gene signature through RNA-sequencing analysis of Gar15-13 treated with DHT using the clinically-annotated METABRIC dataset.
Conclusion: We have demonstrated that activating AR is an effective therapeutic approach in endocrine-resistant breast cancer and that AR activity is tumor suppressive regardless of endocrine-therapy sensitivity.
17 Mar 2019 - 20 Mar 2019