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  • Stender, Joshua DDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA (author)

Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • Cambridge, United States :Cell Press,2017
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-154608
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-154608URI
  • https://doi.org/10.1016/j.molcel.2017.02.008DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Nwachukwu, Jerome CDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Kastrati, IridaDepartment of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA (author)
  • Kim, YohanDepartment of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada (author)
  • Strid, TobiasDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA(Swepub:liu)tobst76 (author)
  • Yakir, MaayanDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA (author)
  • Srinivasan, SathishDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Nowak, JasonDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Izard, TinaDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Rangarajan, Erumbi SDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Carlson, Kathryn EDepartment of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA (author)
  • Katzenellenbogen, John ADepartment of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA (author)
  • Yao, Xin-QiuDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA (author)
  • Grant, Barry JDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA (author)
  • Leong, Hon SDepartment of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada (author)
  • Lin, Chin-YoCenter for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA (author)
  • Frasor, JonnaDepartment of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA (author)
  • Nettles, Kendall WDepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (author)
  • Glass, Christopher KDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA (author)
  • Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USADepartment of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA (creator_code:org_t)

Related titles

  • In:Molecular CellCambridge, United States : Cell Press65:6, s. 1122-1135.e51097-27651097-4164

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