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• W2972286212 abstract "Abstract Background Evidence shows that the anticancer effects of microtubule targeting agents are not due solely to their antimitotic activities but also their ability to impair microtubule-dependent oncogenic signalling. Methods The effects of microtubule targeting agents on regulators of TGF-β-induced epithelial-to-mesenchymal transition (EMT) were evaluated in breast cancer cell lines using high content imaging, gene and protein expression, siRNA-mediated knockdown and chromatin immunoprecipitation. Results Microtubule targeting agents rapidly and differentially alter the expression of Snail and Slug, key EMT-promoting transcription factors in breast cancer. Eribulin, vinorelbine and in some cases, ixabepalone, but not paclitaxel, inhibited TGF-β-mediated Snail expression by impairing the microtubule-dependent nuclear localisation of Smad2/3. In contrast, eribulin and vinorelbine promoted a TGF-β-independent increase in Slug in cells with low Smad4. Mechanistically, microtubule depolymerisation induces c-Jun, which consequently increases Slug expression in cells with low Smad4. Conclusion These results identify a mechanism by which eribulin-mediated microtubule disruption could reverse EMT in preclinical models and in patients. Furthermore, high Smad4 levels could serve as a biomarker of this response. This study highlights that microtubule targeting drugs can exert distinct effects on the expression of EMT-regulating transcription factors and that identifying differences among these drugs could lead to their more rational use." @default.
• W2972286212 created "2019-09-12" @default.
• W2972286212 creator A5046557969 @default.
• W2972286212 creator A5049661891 @default.
• W2972286212 creator A5061082353 @default.
• W2972286212 date "2019-09-04" @default.
• W2972286212 modified "2023-10-09" @default.
• W2972286212 title "Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner" @default.
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• W2972286212 doi "https://doi.org/10.1038/s41416-019-0556-9" @default.
• W2972286212 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7884798" @default.
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• W2972286212 hasPublicationYear "2019" @default.
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