2. Academic Validation
  3. NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation

NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation

  • Oncogene. 2022 Feb;41(6):907-919. doi: 10.1038/s41388-021-02142-4.
Le Shu  # 1,  Ao Chen  # 2,  Linrui Li 3,  Lun Yao 3,  Yiduo He 4,  Jianbo Xu 4,  Wei Gu 5 6,  Qiang Li 5 7,  Kun Wang 8,  Tongcun Zhang 2 9,  Guoquan Liu 10 11
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China. [email protected].
  • 2 Institute of Biology and Medicine, College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, 430070, Hubei Province, People's Republic of China.
  • 3 College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, People's Republic of China.
  • 4 College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, People's Republic of China.
  • 5 Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China.
  • 6 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China.
  • 7 Department of Cell Biology, School of Biological Sciences, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China.
  • 8 College of Biomedical Engineering, Hubei University of Medicine, Shiyan, 442000, Hubei Province, People's Republic of China.
  • 9 Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China.
  • 10 Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China. [email protected].
  • 11 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030, Anhui Province, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 34992218 DOI: 10.1038/s41388-021-02142-4
Abstract

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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