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.
Keywords:
breast cancer; crystallography; cytokines; drug resistance; estrogen receptor; inflammation; tamoxifen.
Copyright © 2017 Elsevier Inc. All rights reserved.
MeSH terms
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Antineoplastic Agents, Hormonal / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cytokines / metabolism*
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm* / genetics
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Estrogen Receptor alpha / chemistry
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Estrogen Receptor alpha / drug effects*
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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HeLa Cells
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Hep G2 Cells
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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Inflammation Mediators / metabolism*
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Interleukin-1beta / metabolism
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MCF-7 Cells
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Molecular Dynamics Simulation
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Neoplasms, Hormone-Dependent / drug therapy*
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology
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Phosphorylation
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Protein Conformation
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RNA Interference
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Selective Estrogen Receptor Modulators / pharmacology*
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Tamoxifen / analogs & derivatives*
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Tamoxifen / pharmacology
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Transcription, Genetic
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Transfection
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Tumor Microenvironment
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antineoplastic Agents, Hormonal
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Cytokines
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ESR1 protein, human
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Estrogen Receptor alpha
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IL1B protein, human
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Inflammation Mediators
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Interleukin-1beta
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Selective Estrogen Receptor Modulators
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Tumor Necrosis Factor-alpha
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Tamoxifen
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afimoxifene
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I-kappa B Kinase
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IKBKB protein, human