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イワモト タカユキ
Takayuki Iwamoto
岩本 高行 所属 川崎医科大学 医学部 臨床医学 乳腺甲状腺外科学 職種 講師 |
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| 論文種別 | 原著 |
| 言語種別 | 英語 |
| 査読の有無 | 査読あり |
| 表題 | TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers. |
| 掲載誌名 | 正式名：Molecular oncology 略 称：Mol Oncol ISSNコード：18780261/15747891 |
| 掲載区分 | 国外 |
| 巻・号・頁 | 8(3),pp.508-19 |
| 著者・共著者 | Balázs Győrffy, Giulia Bottai, Jacqueline Lehmann-Che, György Kéri, László Orfi, Takayuki Iwamoto, Christine Desmedt, Giampaolo Bianchini, Nicholas C Turner, Hugues de Thè, Fabrice André, Christos Sotiriou, Gabriel N Hortobagyi, Angelo Di Leo, Lajos Pusztai, Libero Santarpia |
| 発行年月 | 2014/05 |
| 概要 | Breast cancers (BC) carry a complex set of gene mutations that can influence their gene expression and clinical behavior. We aimed to identify genes driven by the TP53 mutation status and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negative BC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC analyses of each gene expression according to TP53 mutation status were performed. The prognostic value of genes with the highest AUC were assessed in a large dataset of untreated, and neoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was the most significant gene correlated with TP53 status, and the most significant prognostic marker in all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated in different BC cell lines. We also assessed the effects of a potent small molecule inhibitor of MPS1, SP600125, alone and in combination with chemotherapy. Consistent with the gene expression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reduction in cell viability and a significant increase in cell death, selectively in TP53-mutated BC cells. Furthermore, the chemical inhibition of MPS1 sensitized BC cells to conventional chemotherapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated kinase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, and that SP600125 warrant further development in future clinical trials. |
| DOI | 10.1016/j.molonc.2013.12.018 |
| PMID | 24462521 |