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Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α

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Abstract

Purpose

The overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types, and targeting Mps1 for tumor therapy has shown great promise in multiple preclinical cancer models. However, the role played by Mps1 in tamoxifen (TAM) resistance in breast cancer has never been reported.

Methods

The sensitivity of breast cancer cells to tamoxifen was analysed in colony formation assays and wound healing assays. Enhanced transactivational activity of estrogen receptor α (ERα) led by Mps1 overexpression was determined by luciferase assays. The interaction between Mps1 and ERα was verified by co-immunoprecipitation and proximity ligation assay. Phosphorylation of ERα by Mps1 was detected by in vitro kinase assay and such phosphorylation process in vivo was proven by co-immunoprecipitation. The potential phosphorylation site(s) of ERα were analyzed by mass spectrometry.

Results

Mps1 determines the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while an Mps1 inhibitor or siMps1 oligos enabled cancer cells to overcome tamoxifen resistance. Mechanistically, Mps1 interacted with estrogen receptor α and stimulated its transactivational activity in a kinase activity-dependent manner. Mps1 was critical for ERα phosphorylation at Thr224 amino acid site. Importantly, Mps1 failed to enhance the transactivational activity of the ERα-T224A mutant.

Conclusion

Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic that can overcome tamoxifen resistance in breast cancer.

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Data availability

The data in this manuscript were generated from original work, and all raw data files can be made available upon request.

Code availability

Not applicable.

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Acknowledgements

We thank the National Natural Science Foundation of China (Grant Nos. 81972696, 81572620 and 81972485).

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81972696, 81572620, and 81972485).

Author information

Author notes

  1. Xuemiao Zhang, Linfei Huang, and Jing Sun have contributed equally to the work.

  2. Congwen Wei, Xiaoli Yang, Yanhong Tai, Yue Han, and Yanhai Wang have jointly supervised the work.

Authors and Affiliations

  1. Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, The Training Site for Postgraduates of Jinzhou Medical University, Jinzhou, 121001, China

    Xuemiao Zhang & Xiaoli Yang

  2. Beijing Institute of Biotechnology, Beijing, 100071, China

    Xuemiao Zhang, Linfei Huang, Jialong Liu, Yulong Zong, Luming Wan, Xiaopan Yang, Yanhong Zhang, Ruzhou Zhao, Jing Liu, Hui Zhong & Congwen Wei

  3. China-Japan Union Hospital of Jilin University, Changchun, 130000, China

    Jing Sun

  4. Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xue Yan & Yue Han

  5. Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, China

    Xiaoli Yang

  6. Clinical School of the Third Medical Center of Chinese PLA General Hospital, Anhui Medical University, Hefei, 230032, China

    Xiaoli Yang

  7. Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100166, China

    Yanhong Tai

  8. Department of Clinical Laboratory, Huhhot First Hospital, Huhhot, 010030, China

    Yanhai Wang

Authors
  1. Xuemiao Zhang
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  2. Linfei Huang
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  3. Jing Sun
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  17. Yanhai Wang
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Contributions

YH W, Y H, YH T, XL Y, and CW W were involved in the conception and design of the study and supervised the manuscript; XM Z drafted manuscript; XM Z, LF H, and J S revised the manuscript; XM Z, LF H, J S, YL Z, and X Y acquired and analyzed the data; JL L, LM W, XP Y, YH Z, RZ Z, J L, and H Z interpreted the data. All the authors have discussed the results and reviewed the manuscript.

Corresponding author

Correspondence to Yanhai Wang.

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Zhang, X., Huang, L., Sun, J. et al. Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α. Breast Cancer Res Treat 202, 595–606 (2023). https://doi.org/10.1007/s10549-023-07098-5

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  • DOI: https://doi.org/10.1007/s10549-023-07098-5

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