Notch3 negatively regulates chemoresistance in breast cancers
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To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial–mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells. Increased Fra1 activated the EMT process. Finally, Notch3 expression was confirmed in clinically chemoresistant samples of breast cancers from patients receiving anthracycline-based chemotherapy. Low expression of Notch3 was an unfavorable predictor of distant relapse-free survival in ER positive breast cancers. Taken together, our findings demonstrate that the Notch3-Fra1 signaling pathway mediates chemoresistance via the EMT.
KeywordsNotch3 Fra1 EMT Chemoresistance Breast cancer
This work was supported by the China National Natural Science Foundation 81572940 and 91439131 to Xin Ma; 31200126 and 31550006 to Dongxu He; 81272358 to Feng Gu; the Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province (BK20140004 to Xin Ma); the Program for New Century Excellent Talents in University of The Ministry of Education of China (NCET-12-0880) to Xin Ma; the National High Technology Research and Development Program (863 Program) of China (SQ2015AA020948) to Xin Ma; and the Fundamental Research Funds for the Central Universities (JUSRP51311A, JUSRP51615B and JUSRP51519) to Xin Ma, Dongxu He and Jin Jian. We thank Dr. IC Bruce for reading the manuscript.
Authors who participated in research design are as follows: X.-T. Gu, D.-X. He, X. Ma, and D-Q. Liu. Authors who conducted experiments are as follows: X.-T. Gu, C.-X. Lu, and Y.-F. Lu. Authors who performed data analysis are as follows: X.-T. Gu and D.-X. He. Authors who wrote or contributed to the writing of the manuscript are as follows: X.-T. Gu and D.-X. He.
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Conflicts of interest
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