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Cellular and Molecular Biology

SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer

British Journal of Cancer (2024)Cite this article

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Abstract

Background

In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer.

Methods

SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding.

Results

SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo.

Conclusion

We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

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Fig. 1: SON expression is associated with ErbB2-positive breast cancer patients with poor outcomes.
Fig. 2: SON is required for ErbB2 and ErbB3 expression.
Fig. 3: SON knockdown causes intron retention of ErbB2 and ErbB3 transcripts.
Fig. 4: SON disruption suppresses ErbB-downstream signalling pathways.
Fig. 5: SON expression is critical for cell proliferation and apoptosis of ErbB-positive cancer cells.
Fig. 6: SON knockdown reduces ErbB2-positive tumour growth in vivo.
Fig. 7: A model of the functional interaction between SON and ErbB.

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Data availability

The Clinical Proteomic Tumour Analysis Consortium (CPTAC2 Retrospective; PDC000173) data are available through the National Cancer Institute Proteomic Data Commons (https://pdc.cancer.gov/).

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Funding

This research was supported by the following grants: China Medical University Ying-Tsai Scholar Fund CMU109-YT-04 and the National Science and Technology Council NSTC 113-2314-B-039-067- (to MT), National Cancer Center grants (NCC-2311410 and 2310390 to JK), the National Institutes of Health (NIH) grants (R01CA236911 and R01HL168659 to EA).

Author information

Author notes

  1. These authors contributed equally: Joshua B. Phillips, Seong-Sik Park.

Authors and Affiliations

  1. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

    Joshua B. Phillips, Sangbin Lim, Ritu Aurora, Jin-Hwan Kim, Anusha Angajala, Joshua K. Stone & Jung-Hyun Kim

  2. Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggido, Republic of Korea

    Seong-Sik Park, Juyoung Cho & Jung-Hyun Kim

  3. Institute of Biochemistry and Molecular Biology, China Medical University, Taichung, Taiwan

    Cheng-Han Lin & Ming Tan

  4. Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Bohye Park, Ssang-Taek Steve Lim & Eun-Young Erin Ahn

  5. Department of Math and Statistics, University of South Alabama, Mobile, AL, USA

    Bin Wang

  6. Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Andrea G. Kahn

  7. O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Ssang-Taek Steve Lim & Eun-Young Erin Ahn

  8. Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan

    Ming Tan

  9. Graduate Institute of Biomedical Sciences and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan

    Ming Tan

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Contributions

JK, EEA and MT developed the study concept and experiment design. SP, JK and JBP performed all the experiments with assistance from CL, JC, SL, RA, JK, AA, BP, JKS and SSL. AGK performed the pathologic analysis of murine tumours. BW provided statistical support. AA performed protein data analyses and interpretation. EEA, MT and JK provided advice throughout the development of the project. EEA, MT, JK, JBP, CHL and SP wrote and revised the manuscript with input from all the authors.

Corresponding authors

Correspondence to Jung-Hyun Kim, Eun-Young Erin Ahn or Ming Tan.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. The animal study was approved by the Institutional Animal Care and Use Committee of the University of South Alabama.

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Phillips, J.B., Park, SS., Lin, CH. et al. SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02853-x

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