Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells.
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.
Sullivan
N J
NJ
Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Sasser
A K
AK
Axel
A E
AE
Vesuna
F
F
Raman
V
V
Ramirez
N
N
Oberyszyn
T M
TM
Hall
B M
BM
D000230:Adenocarcinoma / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D004848:Epithelium / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000096:biosynthesis; D010641:Phenotype; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D014746:Vimentin / Q000096:biosynthesis
D015820:Cadherins; D015850:Interleukin-6; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin