Abstract
In situ models of epithelial-to-mesenchymal transition (EMT)-induced carcinoma develop into metastatic carcinoma, which is associated with drug resistance and disease recurrence in human breast cancer. Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), an essential Ras mediator, has been implicated in cancer development, including cell growth, motility, invasion and apoptosis. Here, we demonstrated that the upregulation of G3BP1 activates the EMT in breast cancer cells. Silencing Smads almost completely blocked this G3BP1-induced EMT, suggesting that this process depends on the Smad signaling pathway. We also found that G3BP1 interacted with the Smad complex. Based on these results, we proposed that G3BP1 might act as a novel co-factor of Smads by regulating their phosphorylation status. Moreover, knockdown of G3BP1 suppressed the mesenchymal phenotype of MDA-MB-231 cells in vitro and suppressed tumor growth and lung metastasis of 4T1 cells in vivo. Our findings identified a novel function of G3BP1 in the progression of breast cancer via activation of the EMT, indicating that G3BP1 might represent a potential therapeutic target for metastatic human breast cancer.
Highlights
In recent years, breast cancer has become the most common and fatal cancer among women worldwide [1]
GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) was overexpressed in many tumor samples compared to healthy tissue [21], the up-regulation of G3BP1 promoted an invasive and metastatic phenotype in non-metastatic breast cancer MCF-7 cells, whereas the down-regulation of G3BP1 suppressed this invasive and metastatic phenotype in metastatic MDA-MB-231 breast cancer cells
Despite previous reports demonstrating that G3BP1 was associated with cell motility and invasion [14, 22], our study provided the first evidence that G3BP1 mediates the epithelial-to-mesenchymal transition (EMT) in breast cancer cells
Summary
Breast cancer has become the most common and fatal cancer among women worldwide [1]. Because the epithelial-to-mesenchymal transition (EMT) can convert benign tumors into invasive and metastatic tumors, it plays a critical role in the regulation of tumor progression and metastasis [2,3,4]. The EMT is a developmental process that enables polarized epithelial cells to undergo multiple biochemical changes to exhibit the phenotypes of mesenchymal cells, including enhanced migratory and invasive capacities and elevated resistance to apoptosis [2]. Many signaling pathways participate in the EMT, including the TGF-β, Notch, Ras, Wnt and Hedgehog signaling pathways [5, 6], and the Smad signaling is necessary for TGF-β-induced EMT. Ectopic Smad or Smad, in combination with Smad, enhances TGF-β-induced EMT, whereas dominantnegative Smad, Smad, or Smad blocks the TGF-βinduced EMT in NMuMG breast epithelial cells [8, 9]
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