title: Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells.
abstract: Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKβ signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stender
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.affiliation: Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strid
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Maayan
authors.initials: M
authors.lastname: Yakir
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Izard
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Erumbi S
authors.initials: ES
authors.lastname: Rangarajan
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Xin-Qiu
authors.initials: XQ
authors.lastname: Yao
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Grant
authors.affiliation: Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Hon S
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
authors.forename: Chin-Yo
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ckg@ucsd.edu.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D061986:MCF-7 Cells; D056004:Molecular Dynamics Simulation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D034622:RNA Interference; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C508585:IL1B protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D020845:Selective Estrogen Receptor Modulators; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; C016601:afimoxifene; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: breast cancer; crystallography; cytokines; drug resistance; estrogen receptor; inflammation; tamoxifen