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

Oncogene. 2009 Aug 20;28(33):2940-7. doi: 10.1038/onc.2009.180. Epub 2009 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cadherins / biosynthesis
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Epithelium / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-6 / physiology*
  • Mesoderm / pathology
  • Mice
  • Neoplasm Transplantation
  • Nuclear Proteins / biosynthesis
  • Phenotype
  • Snail Family Transcription Factors
  • Transcription Factors / biosynthesis
  • Twist-Related Protein 1 / biosynthesis
  • Vimentin / biosynthesis

Substances

  • Cadherins
  • Interleukin-6
  • Nuclear Proteins
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • Vimentin