title: AR collaborates with ERα in aromatase inhibitor-resistant breast cancer.
abstract: Androgen receptor (AR) is an attractive target in breast cancer because of its frequent expression in all the molecular subtypes, especially in estrogen receptor (ER)-positive luminal breast cancers. We have previously shown a role for AR overexpression in tamoxifen resistance. We engineered ER-positive MCF-7 cells to overexpress aromatase and AR (MCF-7 AR Arom cells) to explore the role of AR in aromatase inhibitor (AI) resistance. Androstendione (AD) was used as a substrate for aromatization to estrogen. The nonsteroidal AI anastrazole (Ana) inhibited AD-stimulated growth and ER transcriptional activity in MCF-7 Arom cells, but not in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R and pAKT was found in AR-overexpressing cells, and their inhibitors restored sensitivity to Ana, suggesting that these pathways represent escape survival mechanisms. Sensitivity to Ana was restored with AR antagonists, or the antiestrogen fulvestrant. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR-overexpressing ERα-positive breast cancers. AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, and AR and ERα co-localized in AD + Ana-treated cells, suggesting cooperation between the two receptors. AR-mediated resistance was associated with a failure to block ER transcriptional activity and enhanced up-regulation of AR and ER-responsive gene expression. Clinically, it may be necessary to block both AR and ERα in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways may provide alternative approaches to block escape pathways and restore hormone sensitivity in resistant breast tumors.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Rechoum
authors.forename: Daniela
authors.initials: D
authors.lastname: Rovito
authors.forename: Domenico
authors.initials: D
authors.lastname: Iacopetta
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
mesh_terms: D000077384:Anastrozole; D000735:Androstenedione / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D009570:Nitriles; D011944:Receptors, Androgen; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D000077384:Anastrozole; D000735:Androstenedione; D004958:Estradiol; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt