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

Metastasis is unequivocally the most lethal aspect of breast cancer andthe most prominent feature associated with disease recurrence, the molecular mechanismswhereby epithelial-to-mesenchymal transition (EMT) mediates the initiation andresolution of breast cancer metastasis remains poorly understood. Transforminggrowth factor-β1 (TGF-β1) is a multifunctional cytokine that is intimately involvedin regulating numerous physiological processes, including cellular differentiation,homeostasis and EMT. Recent findings have implicated high levels of TGF-β1 wereassociated with poor outcome, whereas inhibition of TGF-β signaling reduces metastasisin breast cancer, suggesting that the chemo-therapeutic targeting of TGF-β1 orTGF-β signaling may offer new inroads in ameliorating metastatic disease in breastcancer patients. In this study, we showed immunohistochemical evidence for EMT,which is associated with TGF-β1 expression, at the invasion front of breast cancerin vivo. The data also indicated that human breast cancer cell lines, MCF-7 andMDA-MB-435S, of epithelial cell characteristics were induced to undergo EMT byTGF-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 knockdownof 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-β1is dependent on Smad2 signaling and promotes breast cancer cell metastasis.