title: Resveratrol sensitizes tamoxifen in antiestrogen-resistant breast cancer cells with epithelial-mesenchymal transition features.
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.
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. shixiaop@fmmu.edu.cn
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Shi
authors.forename: Shan
authors.initials: S
authors.lastname: Miao
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Zhang
authors.forename: Hua-Zhao
authors.initials: HZ
authors.lastname: Ma
authors.forename: Hai-Li
authors.initials: HL
authors.lastname: Xin
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.forename: Ai-Dong
authors.initials: AD
authors.lastname: Wen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013267:Stilbenes / Q000633:toxicity*; D013629:Tamoxifen / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D051785:Smad Proteins; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D000077185:Resveratrol
references.citation: Nat Rev Cancer. 2007 Jun;7(6):415-28
references.pmid: 17508028
references.citation: Mutat Res. 2003 Feb-Mar;523-524:145-50
references.pmid: 12628512
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Cell. 2011 Jun 10;145(6):926-40
references.pmid: 21663795
references.citation: Ann Oncol. 2007 Jan;18(1):64-69
references.pmid: 17030543
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Int J Cancer. 2006 Jan 15;118(2):290-301
references.pmid: 16080193
references.citation: Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83
references.pmid: 17306316
references.citation: Biochem Biophys Res Commun. 2012 Jan 13;417(2):679-85
references.pmid: 22166209
references.citation: Endocr Relat Cancer. 2006 Dec;13(4):1121-33
references.pmid: 17158758
references.citation: Anticancer Res. 2009 Oct;29(10):3733-40
references.pmid: 19846903
references.citation: Cancer Lett. 2007 Oct 18;256(1):1-24
references.pmid: 17475399
references.citation: Nat Rev Cancer. 2009 Aug;9(8):550-62
references.pmid: 19629070
references.citation: Mutat Res. 2008 Jan-Feb;658(1-2):68-94
references.pmid: 17890139
references.citation: J Bioenerg Biomembr. 2007 Feb;39(1):59-63
references.pmid: 17308975
references.citation: Breast Cancer Res. 2011 Jun 10;13(3):110
references.pmid: 21682933
references.citation: Breast Cancer Res Treat. 2007 Jun;103(2):149-60
references.pmid: 17039263
references.citation: Cancer Res. 2009 Jul 15;69(14):5820-8
references.pmid: 19584296
references.citation: Ann Thorac Surg. 2011 Nov;92(5):1794-804; discussion 1804
references.pmid: 22051275
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1174-80
references.pmid: 15709186
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references.pmid: 19666588
references.citation: Lung Cancer. 2009 Feb;63(2):219-26
references.pmid: 18599154
references.citation: J Pathol. 2005 Oct;207(2):139-46
references.pmid: 16088978
references.citation: Oncologist. 2006 Jul-Aug;11(7):718-31
references.pmid: 16880231
references.citation: Dev Cell. 2008 Jun;14(6):818-29
references.pmid: 18539112
references.citation: Carcinogenesis. 2006 Jul;27(7):1465-74
references.pmid: 16474181
references.citation: Genes Nutr. 2007 Dec;2(3):295-305
references.pmid: 18850184
references.citation: J Natl Cancer Inst. 2006 May 17;98(10):671-80
references.pmid: 16705121
references.citation: Cancer Lett. 2006 Jan 8;231(1):113-22
references.pmid: 16356836
references.citation: J Pharmacol Sci. 2009 Apr;109(4):473-85
references.pmid: 19372630
references.citation: Hum Mol Genet. 2005 Nov 15;14(22):3361-70
references.pmid: 16203744
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2469-76
references.pmid: 15753463
references.citation: Phytother Res. 2005 Jun;19(6):552-5
references.pmid: 16114095
references.citation: Oncogene. 2005 Aug 29;24(37):5764-74
references.pmid: 16123809
references.citation: Clin Cancer Res. 2002 Nov;8(11):3427-32
references.pmid: 12429630