生物
三阴性乳腺癌
癌症研究
癌基因
基因敲除
泛素连接酶
表皮生长因子受体
癌症
乳腺癌
转录因子
细胞周期
泛素
转移
细胞培养
遗传学
基因
作者
Le Shu,Ao Chen,Linrui Li,Lun Yao,Yangbo He,Jianbo Xu,Wei Gu,Qiang Li,Kun Wang,Tongcun Zhang,Guoquan Liu
出处
期刊:Oncogene
[Springer Nature]
日期:2022-01-07
卷期号:41 (6): 907-919
被引量:8
标识
DOI:10.1038/s41388-021-02142-4
摘要
Neuregulin 1 (NRG1), an EGF family member, is expressed in most breast cancers. It promotes breast cancer growth and metastasis in HER2 receptor expressing breast cancer. However, its role in triple-negative breast cancer (TNBC) has not been extensively investigated. In this study, we observed that NRG1 knockdown resulted in the suppression of TNBC cells (MDA-MB-231 cell and MDA-MB-468 cell) metastasis and downregulation of Fra-1 (FOS-like 1, AP-1 transcription factor subunit, which is an overexpressed transcription factor in TNBC and acts as a coordinator of metastasis). In addition, the transcriptional regulation of Fra-1 by NRG1 was mediated by ERK1/2-induced recruitment of c-Myc (MYC proto-oncogene, transcription factor) to the promoter of Fra-1. Furthermore, c-Myc was targeted by an E3 ligase Fbxw7 and its ubiquitination and degradation by Fbxw7 was regulated by NRG1 expression and ERK1/2-mediated Fbxw7 phosphorylation that results in the dissociation and nuclear import of c-Myc. Taken together, the results of our study demonstrated that NRG1 regulates the Fra-1 expression to coordinate the TNBC metastasis via the novel ERK1/2-Fbxw7-c-Myc pathway and targeting NRG1 expression could be a potential therapeutic strategy for TNBC.
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