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Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer

Oncogene (2024)Cite this article

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Abstract

The cancer-associated alternative splicing (AS) events generate cancer-related transcripts which are involved in uncontrolled cell proliferation and drug resistance. However, the key AS variants implicated in tamoxifen (TAM) resistance in breast cancer remain elusive. In the current study, we investigated the landscape of AS events in nine pairs of primary and relapse breast tumors from patients receiving TAM-based therapy. We unrevealed a notable association between the inclusion of exon 7.2 in the 5’untranslated region (5’UTR) of ALDOA mRNA and TAM resistance. Mechanistically, the inclusion of ALDOA exon 7.2 enhances the translation efficiency of the transcript, resulting in increased ALDOA protein expression, mTOR pathway activity, and the promotion of TAM resistance in breast cancer cells. Moreover, the inclusion of exon 7.2 in ALDOA mRNA is mediated by MSI1 via direct interaction. In addition, elevated inclusion of ALDOA exon 7.2 or expression of MSI1 is associated with an unfavorable prognosis in patients undergoing endocrine therapy. Notably, treatment with Aldometanib, an ALDOA inhibitor, effectively restrains the growth of TAM-resistant breast cancer cells in vitro and in vivo. The present study unveils the pivotal role of an AS event in ALDOA, under the regulation of MSI1, in driving TAM resistance in breast cancer. Therefore, this study provides a promising therapeutic avenue targeting ALDOA to combat TAM resistance.

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Fig. 1: Identification of TAM resistance-specific AS changes in breast tumors.
Fig. 2: ES in ALDOA mRNA elevates ALDOA protein expression in TAM-resistant breast cancer cells.
Fig. 3: ALDOA is associated with poor prognosis in breast cancer.
Fig. 4: Knockdown of ALDOA inhibits cell proliferation of TAM-resistant breast cancer cells.
Fig. 5: Knockdown of ALDOA inactivates key pathways driving TAM resistance.
Fig. 6: MSI1 mediates the inclusion of exon 7.2 in ALDOA pre-mRNA.
Fig. 7: Targeting ALDOA is a promising therapeutic approach for TAM-resistant breast cancer.

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Data availability

The data and codes that support the findings of this study can be obtained from the corresponding authors upon reasonable request.

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Acknowledgements

We thank patients for their contribution to the current study. We thank Liping Ye for providing transcriptome data of breast tumors.

Funding

The authors gratefully acknowledge the National Natural Science Foundation of China (82371877 to HS; 32270513 to WD). This study was funded in part by the Dalian Science and Technology Innovation Fund (2021RJ04, WD), the Startup Foundation for Advanced Talents and Science and Technology Innovation Foundation at Yangzhou University (137011856, HS), the Distinguished Doctoral Program of Green Yang Golden Phoenix of Yangzhou City (137012751, SY), the Talent Introduction Fund of Yangzhou University (137012455, SY), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX22_1831 to NW; SJCX23_2043 to XL), the Undergraduate Innovation and Entrepreneurship Program of Nation (X20220739, XCX20230814, YX), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (23KJD310006, SY), and the Jiangsu Provincial Natural Science Foundation (SBK2024040451, SY).

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Author notes

  1. These authors contributed equally: Shiyi Yu, Rui Wu.

Authors and Affiliations

  1. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China

    Shiyi Yu, Yue Si, Zhehao Fan, Yaji Xue, Yongli Chen, Ning Wang, Xinyue Ling, Caili Bi, Yi Yang & Haibo Sun

  2. Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, China

    Shiyi Yu, Yue Si, Zhehao Fan, Yaji Xue, Yongli Chen, Ning Wang, Xinyue Ling, Caili Bi, Yi Yang & Haibo Sun

  3. School of Life Science, Liaoning Normal University, Dalian, China

    Rui Wu & Weibing Dong

  4. Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China

    Ying Wang & Rongmao Sun

  5. The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

    Chang Yao

  6. Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China

    Zheng Wang

  7. Department of Pathology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, China

    Shuangshuang Dong

  8. School of Basic Medical Science, Guangdong Medical University, Dongguan, China

    Zhengyan Liang

  9. Haian Hospital of Traditional Chinese Medicine, Haian, China

    Haibo Sun

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Contributions

HS and SY conceived and coordinated the project. SY, YY, RW, WD, ZF, YS, ZW, NW, CB, XL, and ZL performed experiments and analyzed data. YW, SD, WD, RS, CY, and YY collected clinical samples and performed relevant experiments. SY, YX, and YC acquired bioinformatic data and performed bioinformatic analysis. SY wrote the manuscript which was discussed and edited by all authors.

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Correspondence to Yi Yang, Weibing Dong or Haibo Sun.

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The human subjects, human materials, human data, and the protocol of animal experiments in this study follow the guidelines of the Declaration of Helsinki. The study was approved by and performed under the supervision of the Ethic Committee of Yangzhou University (approval number: YXYLL-2021-08). All patients provided written informed consent.

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Yu, S., Wu, R., Si, Y. et al. Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03134-w

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