Cooperative Dynamics of AR and ER Activity in Breast Cancer

Abstract

Androgen receptor (AR) is expressed in 90% of estrogen receptor alpha–positive (ER⁺) breast tumors, but its role in tumor growth and progression remains controversial. Use of two anti-androgens that inhibit AR nuclear localization, enzalutamide and MJC13, revealed that AR is required for maximum ER genomic binding. Here, a novel global examination of AR chromatin binding found that estradiol induced AR binding at unique sites compared with dihydrotestosterone (DHT). Estradiol-induced AR-binding sites were enriched for estrogen response elements and had significant overlap with ER-binding sites. Furthermore, AR inhibition reduced baseline and estradiol-mediated proliferation in multiple ER⁺/AR⁺ breast cancer cell lines, and synergized with tamoxifen and fulvestrant. In vivo, enzalutamide significantly reduced viability of tamoxifen-resistant MCF7 xenograft tumors and an ER⁺/AR⁺ patient-derived model. Enzalutamide also reduced metastatic burden following cardiac injection. Finally, in a comparison of ER⁺/AR⁺ primary tumors versus patient-matched local recurrences or distant metastases, AR expression was often maintained even when ER was reduced or absent. These data provide preclinical evidence that anti-androgens that inhibit AR nuclear localization affect both AR and ER, and are effective in combination with current breast cancer therapies. In addition, single-agent efficacy may be possible in tumors resistant to traditional endocrine therapy, as clinical specimens of recurrent disease demonstrate AR expression in tumors with absent or refractory ER.

Implications: This study suggests that AR plays a previously unrecognized role in supporting E2-mediated ER activity in ER⁺/AR⁺ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER⁺/AR⁺ breast cancers. Mol Cancer Res; 14(11); 1054–67. ©2016 AACR.