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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 volume 41, pages 907–919 (2022)Cite this article

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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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Fig. 1: Inhibition of NRG1 resulted in the suppression of TNBC migration via downregulation of Fra-1 expression.
Fig. 2: ERK1/2 was involved in the regulation of Fra-1 by NRG1.
Fig. 3: Inhibition of NRG1 led to suppressed recruitment of c-Myc to the Fra-1 promoter via ERK1/2 inactivation.
Fig. 4: Fbxw7-mediated c-Myc ubiquitination is a necessary step in the regulation of Fra-1 by NRG1.
Fig. 5: Inhibition of the NRG1-ERK1/2 axis promoted the interaction between Fbxw7 and c-Myc.
Fig. 6: Inhibition of NRG1 led to the suppression of lung metastasis in vivo.
Fig. 7: Model showing the involvement of the NRG1-mediated pathway in regulating the Fra-1 transcription and metastasis of MDA-MB-231 cancer cells.

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Funding

This study was partially supported financially by the National Natural Science Foundation of China (31372418, GL) and Bengbu Medical College Scientific and Technology Self-Innovation Foundation Program (No. BYKC2003, GL).

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Author notes

  1. These authors contributed equally: Le Shu, Ao Chen.

Authors and Affiliations

  1. Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, 233030, Anhui Province, People’s Republic of China

    Le Shu, Wei Gu, Qiang Li & Guoquan Liu

  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

    Ao Chen & Tongcun Zhang

  3. College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, People’s Republic of China

    Linrui Li & Lun Yao

  4. College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, People’s Republic of China

    Yiduo He & Jianbo Xu

  5. Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030, Anhui Province, People’s Republic of China

    Wei Gu & Guoquan Liu

  6. Department of Cell Biology, School of Biological Sciences, Bengbu Medical College, Bengbu, 233030, Anhui Province, People’s Republic of China

    Qiang Li

  7. College of Biomedical Engineering, Hubei University of Medicine, Shiyan, 442000, Hubei Province, People’s Republic of China

    Kun Wang

  8. 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

    Tongcun Zhang

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Contributions

LS, GL, and TZ conceived and designed the study. AC, WG, QL, YH, LY, JX, KW, and LL contributed to the carrying out the experiments. GL, LS, and AC contributed to the data analysis. LS wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Le Shu or Guoquan Liu.

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This study was reviewed and approved by the Ethnics Committees of Bengbu Medical College (Bengbu, China). The study was conducted in accordance with the Institutional Animal Care and Use Committee.

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Shu, L., Chen, A., Li, L. et al. 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 41, 907–919 (2022). https://doi.org/10.1038/s41388-021-02142-4

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