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Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
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2017 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 65, no 6, p. 1122-1135.e5, article id S1097-2765(17)30122-3Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Cambridge, United States: Cell Press , 2017. Vol. 65, no 6, p. 1122-1135.e5, article id S1097-2765(17)30122-3
Keywords [en]
breast cancer, crystallography, cytokines, drug resistance, estrogen receptor, inflammation, tamoxifen
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-154608DOI: 10.1016/j.molcel.2017.02.008ISI: 000396431900017PubMedID: 28306507Scopus ID: 2-s2.0-85015279462OAI: oai:DiVA.org:liu-154608DiVA, id: diva2:1290774
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-03-05Bibliographically approved

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Strid, Tobias
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