Eribulin rapidly inhibits TGF-ß-induced Snail expression and can induce Slug expression in a Smad4-dependent manner.
Br J Cancer
; 121(7): 611-621, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-31481735
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-ß-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-ß-mediated Snail expression by impairing the microtubule-dependent nuclear localisation of Smad2/3. In contrast, eribulin and vinorelbine promoted a TGF-ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
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Transforming Growth Factor beta
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Smad4 Protein
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Snail Family Transcription Factors
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Furans
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Ketones
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Microtubules
Type of study:
Prognostic_studies
Limits:
Female
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Humans
Language:
En
Journal:
Br J Cancer
Year:
2019
Document type:
Article
Affiliation country:
Country of publication: