Disulfiram inhibits TGF-β-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-κB/Snail pathway.

Dan Han,Yin Xiao,Gang Wu,Tao Zhang,Liling Zhang,Fang Zhu,Chan Chang,Qiuhui Li

doi:10.18632/oncotarget.5723

Abstract

Disulfiram (DSF), an anti-alcoholism drug, has been reported as an inhibitor of NF-κB. NF-κB is involved in epithelial-mesenchymal transition (EMT) and self-renewal of breast cancer stem cells (CSCs). In this study, we treated MCF-7 and MDA-MB-231 breast cancer cells with TGF-β to induce EMT and cancer stem-like features and studied whether DSF can reverse this process. We found that DSF inhibited TGF-β induced EMT in breast cancer cells in a dose-dependent manner. Also, DSF inhibited EMT-associated stem-like features, migration and invasion of tumor cells as well as tumor growth in xenograft model. The activation of NF-κB was linked with EMT and stem-like cells. We conclude that DSF can suppress NF-κB activity and downregulate ERK/NF-κB/Snail pathway, leading to reverse EMT and stem-like features. Our data suggest that DSF inhibits EMT and stem-like properties in breast cancer cells associated with inhibition of the ERK/NF-κB/Snail pathway.

Highlights

Breast cancer is the most common malignant tumor in female, and metastasis is the leading cause of cancer related death [1]
We found that DSF inhibited transforming growth factor (TGF)-β induced epithelial-mesenchymal transition (EMT) in breast cancer cells in a dose-dependent manner
DSF significantly suppressed the TGF-β induced upregulation of vimentin and N-cadherin as well as downregulation of E-cadherin in a dose-dependency (Figure 1C and 1D). These findings suggest that DSF can inhibit TGF-β induced EMT by modifying the expression of EMT related proteins

Summary

Introduction

Breast cancer is the most common malignant tumor in female, and metastasis is the leading cause of cancer related death [1]. In spite of many advances such as HER2 or VEGF targeting medicines, median overall survival of patients with advanced breast cancer is still only 2–3 years [2]. There is a great need for novel mechanistic understanding of tumor metastasis, which would be critical for developing more effective therapies. Epithelial–mesenchymal transition (EMT) is a fundamental process for morphogenesis during embryonic development, tissue remodeling and wound healing [3, 4], but more recently it has been implicated in cancer progression and metastasis [5,6,7]. The most prominent characteristic of EMT is the morphological alteration from epithelial to mesenchymal, which is often accompanied by the downregulated expression of epithelial markers, such as

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Results

Conclusion