RETRACTED: Inhibition of Notch1 reverses EMT and chemoresistance to cisplatin via direct downregulation of MCAM in triple‐negative breast cancer cells

• Published in: International journal of cancer 2020-07, Vol.147 (2), p.490-504
• Main Authors: Zeng, De, Liang, Yuan‐Ke, Xiao, Ying‐Sheng, Wei, Xiao‐Long, Lin, Hao‐Yu, Wu, Yang, Bai, Jing‐Wen, Chen, Min, Zhang, Guo‐Jun
• Format: Article
• Language: English
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32911

Resistance to chemotherapy continues to be a critical issue in the clinical therapy of triple‐negative breast cancer (TNBC). Epithelial–mesenchymal transition (EMT) is thought to contribute to chemoresistance in several cancer types, including breast cancer. Identification of the key signaling pathway that regulates the EMT program and contributes to chemoresistance in TNBC will provide a novel strategy to overcome chemoresistance in this subtype of cancer. Herein, we demonstrate that Notch1 positively associates with melanoma cell adhesion molecule (MCAM), a unique EMT activator, in TNBC tissue samples both at mRNA and protein levels. High expression of Notch1 and MCAM both predicts a poor survival in basal‐like/TNBC patients, particularly in those treated with chemotherapy. The expression of Notch1 and MCAM in MDA‐MB‐231 cells gradually increases in a time‐dependent manner when exposing to low dose cisplatin. Moreover, the expressions of Notch1 and MCAM in cisplatin‐resistant MDA‐MB‐231 cells are significantly higher than wild‐type counterparts. Notch1 promotes EMT and chemoresistance, as well as invasion and proliferation of TNBC cells via direct activating MCAM promoter. Inhibition of Notch1 significantly downregulates MCAM expression, resulting in the reversion of EMT and chemoresistance to cisplatin in TNBC cells. Our study reveals the regulatory mechanism of the Notch1 pathway and MCAM in TNBC and suggesting that targeting the Notch1/MCAM axis, in conjunction with conventional chemotherapies, might be a potential avenue to enhance the therapeutic efficacy for patients with TNBC. What's new? Epithelial‐mesenchymal transition (EMT) likely contributes to chemoresistance in triple‐negative breast cancers (TNBC), but the underlying mechanisms remain unclear. Here, the expression of Notch1 positively associated with melanoma cell adhesion molecule (MCAM), a unique EMT activator, in TNBC tissue samples. High expression of Notch1 and MCAM predicted poor survival, particularly in patients treated with chemotherapy. Notch1 and MCAM levels were significantly higher in cisplatin‐resistant than wild‐type TNBC cells. The findings suggest that Notch1 regulates MCAM in EMT and contributes to cisplatin resistance in TNBC. Targeting the Notch1/MCAM axis might be a potential avenue to enhance therapeutic efficacy in patients with TNBC.