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Cited by 757Cancer Cells and MetastasisTGF-β signaling in diseasesCytokine Signaling Pathways and Interactions

Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells

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Sullivan, N J, Sasser, A K, Axel, A E, Vesuna, F, Raman, V, Ramirez, N, Oberyszyn, T M, Hall, B M·2009·Oncogene
DOI 10.1038/onc.2009.180PMC PMC5576031
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Abstract

Breast tumor interleukin-6 (IL-6) levels increase with tumor grade, and elevated serum IL-6 correlates with poor breast cancer patient survival. Epithelial-mesenchymal transition (EMT) phenotypes such as impaired E-cadherin expression or aberrant Vimentin induction are associated with enhanced metastasis and unfavorable clinical outcome in breast cancer. Despite this fact, few tumor microenvironment-derived extracellular signaling factors capable of provoking such a phenotypic transition have been identified. In this study, we showed that IL-6 promoted E-cadherin repression among a panel of estrogen receptor-alpha-positive human breast cancer cells. Furthermore, ectopic stable IL-6 expressing MCF-7 breast adenocarcinoma cells (MCF-7(IL-6)) exhibited an EMT phenotype characterized by impaired E-cadherin expression and induction of Vimentin, N-cadherin, Snail and Twist. MCF-7(IL-6) cells formed xenograft tumors that displayed loss of E-cadherin, robust Vimentin induction, increased proliferative indices, advanced tumor grade and undifferentiated histology. Finally, we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin. To our knowledge, this is the first study that shows IL-6 as an inducer of an EMT phenotype in breast cancer cells and implicates its potential to promote breast cancer metastasis.

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  • The IL-6-STAT3 pathway is involved in the epithelial-mesenchymal transition, tumor migration, cancer stemness and the induction of HIF-1α and VEGF, two key players for angiogenesis.

    “The IL-6–STAT3 pathway is involved in the epithelial–mesenchymal transition (EMT) (131, 132), tumor migration (133), cancer stemness (130, 134, 135) and the induction of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), two key players for angiogenesis (136–140).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [131]

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References 38 · Cited by 757

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  1. Bachelot T Ray-Coquard I Menetrier-Caux C Rastkha M Duc A Blay JY 2003 Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients Br J Cancer 88 1721 1726 12771987 PMC2377148
  2. Barton BE Karras JG Murphy TF Barton A Huang HF 2004 Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines Mol Cancer Ther 3 11 20 14749471
  3. Blaskovich MA Sun J Cantor A Turkson J Jove R Sebti SM 2003 Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice Cancer Res 63 1270 1279 12649187
  4. Chavey C Bibeau F Gourgou-Bourgade S Burlinchon S Boissiere F Laune D 2007 Oestrogen receptor negative breast cancers exhibit high cytokine content Breast Cancer Res 9 R15 17261184 PMC1851386
  5. Cheng GZ Zhang WZ Sun M Wang Q Coppola D Mansour M 2008 Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function J Biol Chem 283 14665 14673 18353781 PMC2386910
  6. Conze D Weiss L Regen PS Bhushan A Weaver D Johnson P 2001 Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells Cancer Res 61 8851 8858 11751408
  7. Elston CW Ellis IO 1991 Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up Histopathology 19 403 410 1757079
  8. Gritsko T Williams A Turkson J Kaneko S Bowman T Huang M 2006 Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells Clin Cancer Res 12 11 19 16397018
  9. Heimann R Hellman S 2000 Individual characterisation of the metastatic capacity of human breast carcinoma Eur J Cancer 36 1631 1639 10959049
  10. Jiang XP Yang DC Elliott RL Head JF 2000 Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status Cytokine 12 458 465 10857759
  11. Karnoub AE Dash AB Vo AP Sullivan A Brooks MW Bell GW 2007 Mesenchymal stem cells within tumour stroma promote breast cancer metastasis Nature 449 557 563 17914389
  12. Kishimoto T 2006 Interleukin-6: discovery of a pleiotropic cytokine Arthritis Res Ther 8 S2 PMC3226075 16899106
  13. Kozlowski L Zakrzewska I Tokajuk P Wojtukiewicz MZ 2003 Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients Rocz Akad Med Bialymst 48 82 84 14737948
  14. Lebret SC Newgreen DF Thompson EW Ackland ML 2007 Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors Breast Cancer Res 9 R19 17311675 PMC1851381
  15. Lin Q Lai R Chirieac LR Li C Thomazy VA Grammatikakis I 2005 Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells Am J Pathol 167 969 980 16192633 PMC1603671
  16. Massague J 2008 TGFbeta in cancer Cell 134 215 230 18662538 PMC3512574
  17. Mironchik Y Winnard PT Jr Vesuna F Kato Y Wildes F Pathak AP 2005 Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer Cancer Res 65 10801 10809 16322226 PMC5575828
  18. Moody SE Perez D Pan TC Sarkisian CJ Portocarrero CP Sterner CJ 2005 The transcriptional repressor Snail promotes mammary tumor recurrence Cancer Cell 8 197 209 16169465
  19. Nicolini A Carpi A Rossi G 2006 Cytokines in breast cancer Cytokine Growth Factor Rev 17 325 337 16931107
  20. Oka H Shiozaki H Kobayashi K Inoue M Tahara H Kobayashi T 1993 Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis Cancer Res 53 1696 1701 8453644
  21. Paszek MJ Zahir N Johnson KR Lakins JN Rozenberg GI Gefen A 2005 Tensional homeostasis and the malignant phenotype Cancer Cell 8 241 254 16169468
  22. Pedersen KB Nesland JM Fodstad O Maelandsmo GM 2002 Expression of S100A4, E-cadherin, alpha- and beta-catenin in breast cancer biopsies Br J Cancer 87 1281 1286 12439718 PMC2408909
  23. Salgado R Junius S Benoy I Van Dam P Vermeulen P Van Marck E 2003 Circulating interleukin-6 predicts survival in patients with metastatic breast cancer Int J Cancer 103 642 646 12494472
  24. Sansone P Storci G Tavolari S Guarnieri T Giovannini C Taffurelli M 2007 IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland J Clin Invest 117 3988 4002 18060036 PMC2096439
  25. Sarrio D Rodriguez-Pinilla SM Hardisson D Cano A Moreno-Bueno G Palacios J 2008 Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype Cancer Res 68 989 997 18281472
  26. Sasser AK Mundy BL Smith KM Studebaker AW Axel AE Haidet AM 2007a Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments Cancer Lett 254 255 264 17467167
  27. Singh A Purohit A Ghilchik MW Reed MJ 1999 The regulation of aromatase activity in breast fibroblasts: the role of interleukin-6 and prostaglandin E2 Endocr Relat Cancer 6 139 147 10731102
  28. Studebaker AW Storci G Werbeck JL Sansone P Sasser AK Tavolari S 2008 Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner Cancer Res 68 9087 9095 18974155
  29. Thiery JP 2002 Epithelial–mesenchymal transitions in tumour progression Nat Rev Cancer 2 442 454 12189386
  30. Thiery JP Sleeman JP 2006 Complex networks orchestrate epithelial–mesenchymal transitions Nat Rev Mol Cell Biol 7 131 142 16493418
  31. Thuault S Valcourt U Petersen M Manfioletti G Heldin CH Moustakas A 2006 Transforming growth factor-beta employs HMGA2 to elicit epithelial–mesenchymal transition J Cell Biol 174 175 183 16831886 PMC2064178
  32. van Dam M Mullberg J Schooltink H Stoyan T Brakenhoff JP Graeve L 1993 Structure-function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding J Biol Chem 268 15285 15290 8325898
  33. Waerner T Alacakaptan M Tamir I Oberauer R Gal A Brabletz T 2006 ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells Cancer Cell 10 227 239 16959614
  34. Yang J Weinberg RA 2008 Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis Dev Cell 14 818 829 18539112
  35. Zhang GJ Adachi I 1999 Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma Anticancer Res 19 1427 1432 10365118

Authors
Sullivan, N. J., Sasser, A. K., Axel, A. E., Vesuna, F., Raman, V, Ramirez, N., Oberyszyn, T. M., & Hall, B. M.
Affiliations
  • Nationwide Children's Hospital (US)
  • Johns Hopkins University (US)
  • The Ohio State University (US)
Corresponding author
Oberyszyn, T M
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2009-07-06
Volume
28
Issue
33
Pages
2940-2947
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2009.180
PMC
PMC5576031
OpenAlex
W1986834354
Cited by
757
References
38
Citations by year
2026: 11 · 2025: 30 · 2024: 23 · 2023: 50 · 2022: 39 · 2021: 49 · 2020: 49 · 2019: 54 · 2018: 53 · 2017: 72 · 2016: 52 · 2015: 55 · 2014: 59 · 2013: 52 · 2012: 37
FWCI
18.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Elsa U. Pardee Foundation
  • National Cancer Institute (R01CA097226)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, epithelial-mesenchymal transition, breast cancer, E-cadherin repression, vimentin, N-cadherin, snails, Twist, STAT3 activation, tumor microenvironment, metastasis, MCF-7 cells, tumor xenografts, estrogen receptor alpha-positive breast cancer
MeSH terms
Snail Family Transcription Factors, Adenocarcinoma, Animals, Breast Neoplasms, Epithelium, Female, Humans, Mesoderm, Neoplasm Transplantation, Nuclear Proteins, Phenotype, Transcription Factors, Vimentin, Cadherins, Interleukin-6, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice, Twist-Related Protein 1

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