期刊
CANCER LETTERS
卷 440, 期 -, 页码 156-167出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.09.031
关键词
Breast cancer; Chemoresistance; Notch signaling pathway; MVP
类别
资金
- Major International Collaborative Research Project of NSFC [81320108015]
- Guangdong Provincial Key Laboratory on Breast Cancer Diagnosis and Treatment Research, Research Team Project of Natural Science Foundation of Guangdong Province [2016A030312008]
- Xiamen University
Resistance to chemotherapy remains a significant problem in the treatment of breast cancer, especially for triple negative breast cancer (TNBC), in which standard systemic therapy is currently limited to chemotherapeutic agents. Our study aimed to better understand the molecular mechanisms that lead to failure of chemotherapy in TNBC. Herein, we observed elevated expression of Notch1 and major vault protein (MVP) in MDA-MB-231DDPR cells compared to their parental counterparts. We demonstrated that Notch1 could positively regulate the expression of MVP. Also, Notch1 intracellular domain (ICD) was capable of binding to CBF-1 on the promoter of MVP to drive its transcription, resulting in activation of AKT pathway and promoting the progress of epithelial to mesenchymal transition (EMT). Conversely, silencing of Notch1 and MVP suppressed AKT pathway, reduced EMT and enhanced the sensitivity of TNBC cells to cisplatin and doxorubicin. Survival analysis indicated that the MVP was closely related to shorter recurrence-free survival (RFS) in patients with TNBC. Collectively, this study provides evidence that Notch1 activates AKT pathway and promotes EMT partly through direct activation of MVP. Targeting Notch1/MVP pathway appears to have potential in overcoming chemoresistance in TNBC.
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