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

NJ Sullivan, AK Sasser, AE Axel, F Vesuna, V Raman… - Oncogene, 2009 - nature.com
NJ Sullivan, AK Sasser, AE Axel, F Vesuna, V Raman, N Ramirez, TM Oberyszyn, BM Hall
Oncogene, 2009nature.com
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 …
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-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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