Transforming growth factor-β 1 enhances the invasiveness of breast cancer cells by inducing a Smad2-dependent epithelial-to-mesenchymal transition

Oncol Rep. 2013 Jan;29(1):219-25. doi: 10.3892/or.2012.2111. Epub 2012 Oct 30.

Abstract

Metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby epithelial-to-mesenchymal transition (EMT) mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis and EMT. Recent findings have implicated high levels of TGF-β1 were associated with poor outcome, whereas inhibition of TGF-β signaling reduces metastasis in breast cancer, suggesting that the chemo-therapeutic targeting of TGF-β1 or TGF-β signaling may offer new inroads in ameliorating metastatic disease in breast cancer patients. In this study, we showed immunohistochemical evidence for EMT, which is associated with TGF-β1 expression, at the invasion front of breast cancer in vivo. The data also indicated that human breast cancer cell lines, MCF-7 and MDA-MB-435S, of epithelial cell characteristics were induced to undergo EMT by TGF-β1 and dependent on the Smad2 signaling pathway. Following TGF-β1 treatment, cells showed dramatic morphological changes assessed by phase contrast microscopy, accompanied by decreased epithelial marker and increased mesenchymal markers. Importantly, cell invasion was also enhanced in the EMT process, while knockdown of the Smad2 gene by silencing siRNA partially inhibited these effects in MDA-MB435S (P<0.05). These data suggested that EMT of breast cancer induced by TGF-β1 is dependent on Smad2 signaling and promotes breast cancer cell metastasis.

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cell Movement*
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Neoplasm Invasiveness
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Smad2 Protein / antagonists & inhibitors
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Tissue Array Analysis
  • Transforming Growth Factor beta1 / metabolism*
  • Tumor Cells, Cultured

Substances

  • RNA, Small Interfering
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta1