Cooperative Dynamics of AR and ER Activity in Breast Cancer

Mol Cancer Res. 2016 Nov;14(11):1054-1067. doi: 10.1158/1541-7786.MCR-16-0167. Epub 2016 Aug 26.


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.

MeSH terms

  • Anilides / pharmacology
  • Benzamides
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Chromatin / metabolism*
  • Cyclohexanes / pharmacology
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects*
  • Estradiol
  • Female
  • Humans
  • MCF-7 Cells
  • Nitriles
  • Phenylthiohydantoin / administration & dosage
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Receptors, Androgen / metabolism*
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Tamoxifen / administration & dosage*
  • Tamoxifen / pharmacology


  • AR protein, human
  • Anilides
  • Benzamides
  • Chromatin
  • Cyclohexanes
  • N-(2,3-dichlorophenyl)cyclohexanecarboxamide
  • Nitriles
  • Receptors, Androgen
  • Receptors, Estrogen
  • Tamoxifen
  • Phenylthiohydantoin
  • Estradiol
  • enzalutamide