Gu Xiaoting, Lu Chunxiao, He Dongxu, Lu Yangfan, Jin Jian, Liu Dequan, Ma Xin
School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd, Wuxi, Jiangsu, 214122, China.
National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi, 214122, China.
Tumour Biol. 2016 Dec;37:15825–15833. doi: 10.1007/s13277-016-5412-4. Epub 2016 Oct 14.
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.
为了明确NOTCH信号通路在化疗耐药及相关上皮-间质转化（EMT）发生发展中的作用，我们研究了Notch3对阿霉素（ADM）耐药的人乳腺癌细胞（MCF-7/ADM细胞）的影响。我们发现Notch3在MCF-7/ADM细胞中表达下调并参与其化疗耐药，而Notch3的强制表达可逆转化疗耐药。此外，Fos相关抗原1（Fra1）受Notch3负调控，在MCF-7/ADM细胞中高表达。Fra1表达增加激活了EMT过程。最后，在接受蒽环类化疗的乳腺癌患者临床化疗耐药样本中证实了Notch3的表达。Notch3低表达是雌激素受体阳性乳腺癌远处无复发生存的不良预测指标。综上所述，我们的研究结果表明，Notch3-Fra1信号通路通过EMT介导化疗耐药。
