title: 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.
  
  
  
  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.
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Nicholas C
authors: NC
authors: D'Amato
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Michael A
authors: MA
authors: Gordon
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Beatrice
authors: B
authors: Babbs
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Nicole S
authors: NS
authors: Spoelstra
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Kiel T
authors: KT
authors: Carson Butterfield
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Kathleen C
authors: KC
authors: Torkko
authors: Medivation, Inc., San Francisco, California.
authors: Vernon T
authors: VT
authors: Phan
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Valerie N
authors: VN
authors: Barton
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Thomas J
authors: TJ
authors: Rogers
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Carol A
authors: CA
authors: Sartorius
authors: Department of Medicine, Division of Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Anthony
authors: A
authors: Elias
authors: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors: Jason
authors: J
authors: Gertz
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Britta M
authors: BM
authors: Jacobsen
authors: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Jennifer.Richer@ucdenver.edu.
authors: Jennifer K
authors: JK
authors: Richer
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001549:Benzamides; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004958:Estradiol; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000813:Anilides; D001549:Benzamides; D002843:Chromatin; D003510:Cyclohexanes; C000611744:N-(2,3-dichlorophenyl)cyclohexanecarboxamide; D009570:Nitriles; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013629:Tamoxifen; D010669:Phenylthiohydantoin; D004958:Estradiol; C540278:enzalutamide