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Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer
- Source :
- Cell Death & Disease, Cell Death and Disease, Vol 11, Iss 7, Pp 1-15 (2020)
- Publication Year :
- 2020
- Publisher :
- American Society of Clinical Oncology (ASCO), 2020.
-
Abstract
- e13099 Background: YAP and β-catenin play critical roles in the carcinogenesis of several cancers, but their functions in chemoresistance remain unclear in triple-negative breast cancer (TNBC). Herein, we examined the expression and function of the two proteins in the chemoresistance of TNBC. Methods: We examined the expression levels of YAP and β-catenin in TNBC samples by immunohistochemistry (IHC) and their roles in prognosis. Dynamic changes in the two proteins in TNBC tissues were determined by RT-PCR. CCK-8 assays, colony formation assays, flow cytometry, migration assays and nude mouse models were used to investigate the functions of YAP and β-catenin in drug-resistant TNBC cells. The involved signalling pathways were detected by western blot assays. Results: TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression, and changes in the expression of the two proteins might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against TNBC cells in vitro and in vivo. Moreover, YAP and β-catenin were upregulated in docetaxel- or vinorelbine-resistant TNBC cells, while inhibition of YAP or β-catenin enhanced the sensitivity of drug-resistant cells. Interestingly, aspirin, a kind of acetylsalicylic acid, reversed the drug resistance of cells and in combination with aspirin and docetaxel or vinorelbine significantly inhibited the growth of drug-resistant TNBC cells. The involved mechanism is that aspirin impaired YAP or β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP. Conclusions: Both YAP and β-catenin act as key biomarkers of prognosis and anti-microtubule drug resistance in TNBC, and the combined use of aspirin and anti-microtubule drugs inhibits YAP and β-catenin, presenting several promising therapeutic approaches for TNBC treatment.
- Subjects :
- Cancer Research
medicine.medical_treatment
Immunology
Mice, Nude
Cell Cycle Proteins
Triple Negative Breast Neoplasms
medicine.disease_cause
Vinorelbine
Article
Mice
Cellular and Molecular Neuroscience
Breast cancer
In vivo
medicine
Animals
Humans
lcsh:QH573-671
beta Catenin
Triple-negative breast cancer
Chemotherapy
Aspirin
lcsh:Cytology
business.industry
Oncogenes
Cell Biology
medicine.disease
Disease Models, Animal
Oncology
Docetaxel
Drug Resistance, Neoplasm
Catenin
Cancer research
Female
business
Carcinogenesis
Transcription Factors
medicine.drug
Subjects
Details
- ISSN :
- 15277755 and 0732183X
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....89f9212b5bc64b20b6bcd7e9ab29970f