Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial―mesenchymal transition (EMT) to mesenchymal―epithelial transition (MET) states

Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously...

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Bibliographic Details
Published in:British journal of cancer 2014-03, Vol.110 (6), p.1497-1505
Main Authors: YOSHIDA, T, OZAWA, Y, MATSUI, J, KIMURA, T, SATO, Y, KUZNETSOV, G, XU, S, UESUGI, M, AGOULNIK, S, TAYLOR, N, FUNAHASHI, Y
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Breast cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Disease-Free Survival
Epithelial-Mesenchymal Transition - drug effects
Female
Furans - pharmacology
Gene Expression
Genotype & phenotype
Gynecology. Andrology. Obstetrics
Humans
Ketones - pharmacology
Kinases
Lung Neoplasms - drug therapy
Lung Neoplasms - secondary
Mammary gland diseases
Medical sciences
Metastasis
Mice
Mice, Nude
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplasm Metastasis
Phenotype
Phosphorylation
Precision medicine
Translational Therapeutics
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - pathology
Tumors
Xenograft Model Antitumor Assays
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Summary:Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated. Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER-)/progesterone receptor (PR-)/human epithelial growth receptor 2 (HER2-) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting. Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model. Eribulin exerted signif
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.2014.80