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

Stender, Joshua D (author)
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Nwachukwu, Jerome C (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Kastrati, Irida (author)
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
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Kim, Yohan (author)
Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
Strid, Tobias (author)
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Yakir, Maayan (author)
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Srinivasan, Sathish (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Nowak, Jason (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Izard, Tina (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Rangarajan, Erumbi S (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Carlson, Kathryn E (author)
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA
Katzenellenbogen, John A (author)
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA
Yao, Xin-Qiu (author)
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Grant, Barry J (author)
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Leong, Hon S (author)
Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
Lin, Chin-Yo (author)
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
Frasor, Jonna (author)
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
Nettles, Kendall W (author)
Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA
Glass, Christopher K (author)
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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 (creator_code:org_t)
Cambridge, United States : Cell Press, 2017
2017
English.
In: Molecular Cell. - Cambridge, United States : Cell Press. - 1097-2765 .- 1097-4164. ; 65:6, s. 1122-1135.e5
Related links:
http://www.cell.com/...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

Keyword

breast cancer
crystallography
cytokines
drug resistance
estrogen receptor
inflammation
tamoxifen

Publication and Content Type

ref (subject category)
art (subject category)

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