title: Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.
abstract: Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Verena
authors: V
authors: Thewes
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Ronald
authors: R
authors: Simon
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Petra
authors: P
authors: Schroeter
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Magdalena
authors: M
authors: Schlotter
authors: Foundation PATH-Patients' Tumor Bank of Hope, Munich, Germany.
authors: Tobias
authors: T
authors: Anzeneder
authors: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors: Reinhard
authors: R
authors: Büttner
authors: Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
authors: Vladimir
authors: V
authors: Benes
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Guido
authors: G
authors: Sauter
authors: Molecular Biology of Breast Cancer, University Women's Clinic, Heidelberg, Germany.
authors: Barbara
authors: B
authors: Burwinkel
authors: Breast Cancer Group, Cardiff University, Cardiff, United Kingdom.
authors: Robert I
authors: RI
authors: Nicholson
authors: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors: Hans-Peter
authors: HP
authors: Sinn
authors: Gynecologic Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Schneeweiss
authors: Phenex Pharmaceuticals AG, Heidelberg, Germany.
authors: Ulrich
authors: U
authors: Deuschle
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Marc
authors: M
authors: Zapatka
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Stefanie
authors: S
authors: Heck
authors: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. peter.lichter@dkfz.de.
authors: Peter
authors: P
authors: Lichter
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056921:Nuclear Receptor Coactivator 3 / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013629:Tamoxifen / Q000008:administration & dosage; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D056921:Nuclear Receptor Coactivator 3; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000097983:ERRalpha Estrogen-Related Receptor; C506487:ESR1 protein, human; C538866:NCOA3 protein, human