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
- 1.Noritaka Y et al. NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 2008;68:1881–8.Google Scholar
- 8.Zhang Z et al. Notch3 in human breast cancer cell lines regulates osteoblast-cancer cell interactions and osteolytic bone metastasis. Am J Pathol. 2010;177:1459–69.Google Scholar
- 10.Liu L et al. Notch3 is important for TGF-β-induced epithelial–mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1. Cancer Gene Ther. 2014;21:364–72.Google Scholar
- 11.Zhang Q et al. Notch3 functions as a regulator of cell self-renewal by interacting with the β-catenin pathway in hepatocellular carcinoma. Oncotarget. 2015;6:3669.Google Scholar
- 14.Ohashi S et al. A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors. Cancer Res. 2011;71:6836–47.Google Scholar
- 15.Thomson S et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non–small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65:9455–62.Google Scholar
- 16.Sabbah M et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008;11:123–51.Google Scholar
- 19.Desmet CJ et al. Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proc Natl Acad Sci. 2013;110:5139–44.Google Scholar
- 20.Tam WL et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell. 2013;24:347–64.Google Scholar
- 22.Stinson S et al. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal. 2011;4:ra41–1.Google Scholar
- 24.Chen H et al. Extracellular signal–regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res. 2009;69:9228–35.Google Scholar
- 25.Ma X et al. Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells. Proc Natl Acad Sci. 2012;109:16282–7.Google Scholar
- 27.He D et al. A new agent developed by biotransformation of polyphyllin VII inhibits chemoresistance in breast cancer. Oncotarget. 2015;7:31814–24.Google Scholar
- 29.Jiang L et al. MiR-489 regulates chemoresistance in breast cancer via epithelial mesenchymal transition pathway. FEBS Lett. 2014;588:2009–15.Google Scholar
- 30.Hatzis C et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011;305:1873–81.Google Scholar
- 32.Sayan AE et al. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene. 2012;31:1493–503.Google Scholar