Abstract: Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a mesenchymal phenotype. Roles of EMT in embryo development, cancer invasion and metastasis have been extensively reported. Herein, we established tamoxifen-resistant MCF-7/TR breast cancer cells and showed that MCF-7/TR cells underwent EMT driven by enhanced endogenous TGF-β/Smad signaling. Ectopic supplement of TGF-β promoted in MCF-7 cells a mesenchymal and resistant phenotype. In parallel, we demonstrated that resveratrol was capable of synergizing with tamoxifen and triggering apoptosis in MCF-7/TR cells. Further Western blot analysis indicated that the chemosensitizing effects of resveratrol were conferred with its modulation on endogenous TGF-β production and Smad phosphorylation. In particular, 50 μM resveratrol had minor effects on MCF-7/TR cell proliferation, but could significantly attenuate endogenous TGF-β production and the Smad pathway, ultimately leading to reversion of EMT. Collectively, our study highlighted distinct roles of EMT in tamoxifen resistance and resveratrol as a potential agent to overcome acquired tamoxifen resistance. The molecular mechanism of resveratrol chemosensitizing effects is, at least in part, TGF-β/Smad-dependent.
Keywords: breast cancer; tamoxifen; resistance; epithelial-mesenchymal transition; resveratrol
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Shi, X.-P.; Miao, S.; Wu, Y.; Zhang, W.; Zhang, X.-F.; Ma, H.-Z.; Xin, H.-L.; Feng, J.; Wen, A.-D.; Li, Y. Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features. Int. J. Mol. Sci. 2013, 14, 15655-15668.
Shi X-P, Miao S, Wu Y, Zhang W, Zhang X-F, Ma H-Z, Xin H-L, Feng J, Wen A-D, Li Y. Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features. International Journal of Molecular Sciences. 2013; 14(8):15655-15668.
Shi, Xiao-Peng; Miao, Shan; Wu, Yin; Zhang, Wei; Zhang, Xiao-Fang; Ma, Hua-Zhao; Xin, Hai-Li; Feng, Juan; Wen, Ai-Dong; Li, Yan. 2013. "Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features." Int. J. Mol. Sci. 14, no. 8: 15655-15668.