Abstract
PurposeThe aim of this study is to investigate the mechanisms of interactions between TGF-β and Wnt/β-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment.MethodsThe effect of TGF-β on Wnt/β-catenin signaling pathway was examined by using a human Wnt/β-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay.ResultsHER2-overexpressing breast cancer cells treated with TGF-β have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-β-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and β-catenin pathways. The TGF-β-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-β regulating Wnt3 during EMT. Subsequently, TGF-β-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/β-catenin signaling were repressed by the shRNA treatment. TGF-βR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-β-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-β-induced cell invasion significantly in both trastuzumab responsive and resistant cells.ConclusionsOur data demonstrated an important interdependence between TGF-β and Wnt/β-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-β-induced EMT. A83-01 could inhibit the TGF-β-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.
Highlights
TGF-b could act as a tumor suppressor by inhibiting cell proliferation in early carcinogenesis, at late stage, TGF-b pathway could interact with other oncogenic pathways and promote cancer progression [1,2,3,4,5,6]
Purpose The aim of this study is to investigate the mechanisms of interactions between TGF-b and Wnt/bcatenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment
Our data demonstrated an important interdependence between TGF-b and Wnt/b-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells
Summary
TGF-b could act as a tumor suppressor by inhibiting cell proliferation in early carcinogenesis, at late stage, TGF-b pathway could interact with other oncogenic pathways and promote cancer progression [1,2,3,4,5,6]. TGF-b has been shown to induce core transcription factors, Snail, Slug, and Twist, and promote EMT and cell invasiveness in different cell types [7,8,9]. The signal transduction by TGF-b is through its two transmembrane serine/threonine kinase receptors, type II receptor (TGFbRII) and type I receptor (TGFbRI). The TGFbRII activates TGFbRI, which leads to activation of the cellular response to TGF-b [1, 10]. TGF-b-induced EMT could be mediated through both Smad-dependent and Smad-independent pathways [11]. In Smad-dependent pathways, TGF-b induces activation of the receptor
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