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

Oncogene volume 28, pages 2940–2947 (2009)Cite this article

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-α-positive human breast cancer cells. Furthermore, ectopic stable IL-6 expressing MCF-7 breast adenocarcinoma cells (MCF-7IL−6) exhibited an EMT phenotype characterized by impaired E-cadherin expression and induction of Vimentin, N-cadherin, Snail and Twist. MCF-7IL−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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Acknowledgements

This work was funded by the generous support of the Elsa U Pardee Foundation (BH), the American Cancer Society-Ohio Division (BH) and The Research Institute at Nationwide Children's Hospital (BH).

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Authors and Affiliations

  1. Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH, USA

    N J Sullivan, A K Sasser & B M Hall

  2. Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA

    N J Sullivan, A K Sasser, A E Axel, N Ramirez & B M Hall

  3. Department of Radiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    F Vesuna & V Raman

  4. Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA

    N Ramirez & T M Oberyszyn

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  1. N J Sullivan
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  2. A K Sasser
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Correspondence to T M Oberyszyn.

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Sullivan, N., Sasser, A., Axel, A. et al. Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009). https://doi.org/10.1038/onc.2009.180

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  • DOI: https://doi.org/10.1038/onc.2009.180

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