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Int. J. Mol. Sci. 2013, 14(8), 15655-15668; doi:10.3390/ijms140815655

Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features

1
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
2
Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China
3
School of Public Health, Fourth Military Medical University, Xi'an 710032, China
4
Outpatient Department, Institute of Armored Force, Bengbu 233050, China
5
Surgery Pharmacy of Department of Pharceutical Care, General Hospital of PLA, Beijing 100853, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 3 June 2013 / Revised: 17 July 2013 / Accepted: 22 July 2013 / Published: 26 July 2013
(This article belongs to the Special Issue Molecular Bases of Cancer Research)
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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 breast cancer; tamoxifen; resistance; epithelial-mesenchymal transition; resveratrol
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

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.

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