2. Academic Validation
  3. Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α

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

  • Breast Cancer Res Treat. 2023 Sep 11. doi: 10.1007/s10549-023-07098-5.
Xuemiao Zhang # 1 2,  Linfei Huang # 2,  Jing Sun # 3,  Jialong Liu 2,  Yulong Zong 2,  Luming Wan 2,  Xiaopan Yang 2,  Xue Yan 4,  Yanhong Zhang 2,  Ruzhou Zhao 2,  Jing Liu 2,  Hui Zhong 2,  Congwen Wei # 2,  Xiaoli Yang # 1 5 6,  Yanhong Tai # 7,  Yue Han # 4,  Yanhai Wang 8
Affiliations

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.
  • 2 Beijing Institute of Biotechnology, Beijing, 100071, China.
  • 3 China-Japan Union Hospital of Jilin University, Changchun, 130000, China.
  • 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.
  • 5 Department of Clinical Laboratory, The Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
  • 6 Clinical School of the Third Medical Center of Chinese PLA General Hospital, Anhui Medical University, Hefei, 230032, China.
  • 7 Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100166, China.
  • 8 Department of Clinical Laboratory, Huhhot First Hospital, Huhhot, 010030, China. wangyanhai313@163.com.
  • # Contributed equally.
PMID: 37695401 DOI: 10.1007/s10549-023-07098-5
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.

Keywords

Breast cancer; Estrogen receptor α; Monopolar Spindle 1; Tamoxifen resistance.

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