Zhang Xuemiao, Huang Linfei, Sun Jing, Liu Jialong, Zong Yulong, Wan Luming, Yang Xiaopan, Yan Xue, Zhang Yanhong, Zhao Ruzhou, Liu Jing, Zhong Hui, Wei Congwen, Yang Xiaoli, Tai Yanhong, Han Yue, Wang Yanhai
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.
Beijing Institute of Biotechnology, Beijing, 100071, China.
Breast Cancer Res Treat. 2023 Dec;202(3):595-606. doi: 10.1007/s10549-023-07098-5. Epub 2023 Sep 11.
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.
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.
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.
Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic that can overcome tamoxifen resistance in breast cancer.
有研究已证实有丝分裂激酶单极纺锤体1（Mps1）在多种肿瘤类型中均有过表达，在多个临床前癌症模型中，以Mps1为靶点进行肿瘤治疗已显示出巨大前景。然而，Mps1在乳腺癌对他莫昔芬（TAM）耐药中所起的作用尚未见报道。
通过集落形成试验和伤口愈合试验分析乳腺癌细胞对他莫昔芬的敏感性。通过荧光素酶试验测定由Mps1过表达导致的雌激素受体α（ERα）转录激活活性增强情况。通过免疫共沉淀和邻近连接试验验证Mps1与ERα之间的相互作用。通过体外激酶试验检测Mps1对ERα的磷酸化作用，并通过免疫共沉淀证实体内的这种磷酸化过程。通过质谱分析ERα的潜在磷酸化位点。
Mps1决定乳腺癌细胞对他莫昔芬治疗的敏感性。Mps1过表达使乳腺癌细胞对他莫昔芬更具耐药性，而Mps1抑制剂或siMps1寡核苷酸可使癌细胞克服他莫昔芬耐药性。从机制上讲，Mps1与雌激素受体α相互作用，并以激酶活性依赖的方式刺激其转录激活活性。Mps1对ERα第224位苏氨酸位点的磷酸化至关重要。重要的是，Mps1无法增强ERα-T224A突变体的转录激活活性。
Mps1导致乳腺癌对他莫昔芬耐药，是一种可克服乳腺癌他莫昔芬耐药性的潜在治疗靶点。
