Abstract
Epithelial-mesenchymal transition (EMT) can contribute to tumor invasion, metastasis, and resistance to chemotherapy or hormone therapy. EMT may be induced by a variety of growth factors, such as epidermal growth factor (EGF). Most studies regarding EMT have focused on TGF-β-Smads signaling. The mechanism of EGF-induced EMT via activation of the Smad2/3 in breast cancer cells, MCF-7 and MDA-MB-231, remains unclear. The expression levels of Snail, vimentin, and fibronectin were increased by EGF treatment in a time-dependent manner, while the expression level of E-cadherin was decreased. EGF-induced nuclear co-localization of phospho-Smad2/3 and Snail and cancer cell migration were inhibited by pretreatment with an ERK1/2 inhibitor, PD98059 and a phospho-Smad2 inhibitor, SB203580. Knockdown of Smad2/3 expression suppressed EGF-induced expressions of Snail, vimentin, fibronectin, and cancer cell invasion, suggesting an acquisition of the mesenchymal and migratory phenotype in less aggressive MCF-7 cells. Moreover, MDA-MB-231 cells were shown that EGF-induced EMT, and cell invasion through ERK1/2-phospho-Smad2/3-Snail signaling pathway. We have discovered that EGF-stimulated activation of Smad2/3 upregulated several key EMT markers, inhibited E-cadherin expression, promoted EMT, enhanced migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells. Identification of this molecular mechanism may provide new molecular targets for the development of therapies for metastatic breast cancer.
Highlights
Most cancer deaths are largely caused by metastases rather than their primary tumors [1, 2]
We examined the effect of epidermal growth factor (EGF) on the activation of Smad2/3, two molecules that mediate the transforming growth factor-β (TGF-β) signaling pathway
We further examined the expression of E-cadherin by immunofluorescence staining and found that the E-cadherin expression level was decreased in EGFtreated cells compared to its expression level control cells (Figure 2B)
Summary
Most cancer deaths are largely caused by metastases rather than their primary tumors [1, 2]. Morphological changes of epithelial cells into mesenchymal cells, termed epithelial-mesenchymal transition (EMT), can be observed in invasive cancer development and during normal processes such as embryogenesis [3]. These changes include losses of polarity and cell-cell adhesion as well as the ability of mesenchymal cell to migrate away from the point of origin [4]. The process of EMT induced by transforming growth factor-β (TGF-β) is well-established as a critical mechanism of tumor progression [8,9,10]. Binding of TGF-β to its receptor leads to activation of the transcription factors, Smad2/3, that can form complexes with Smad in the cytoplasm and translocate into the nucleus where the factors can induce transcription of target genes [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
