title: Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer.
abstract: Glucocorticoids (GCs) have been widely used as coadjuvants in the treatment of solid tumours, but GC treatment may be associated with poor pharmacotherapeutic response or prognosis. The genomic action of GC in these tumours is largely unknown. Here we find that dexamethasone (Dex, a synthetic GC)-regulated genes in triple-negative breast cancer (TNBC) cells are associated with drug resistance. Importantly, these GC-regulated genes are aberrantly expressed in TNBC patients and are associated with unfavourable clinical outcomes. Interestingly, in TNBC cells, Compound A (CpdA, a selective GR modulator) only regulates a small number of genes not involved in carcinogenesis and therapy resistance. Mechanistic studies using a ChIP-exo approach reveal that Dex- but not CpdA-liganded glucocorticoid receptor (GR) binds to a single glucocorticoid response element (GRE), which drives the expression of pro-tumorigenic genes. Our data suggest that development of safe coadjuvant therapy should consider the distinct genomic function between Dex- and CpdA-liganded GR.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0002-6117-4704
authors.initials: B
authors.lastname: Sunkel
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Departments of Pathology and Urology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.|State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D017239:Paclitaxel / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D014439:Tyramine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D005938:Glucocorticoids; D008024:Ligands; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D017239:Paclitaxel; D014439:Tyramine