TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers

Győrffy, Balázs and Bottai, Giulia and Lehmann-Che, Jacqueline and Kéri, György and Őrfi, László and Iwamoto, Takayuki and Desmedt, Christine and Bianchini, Giampaolo and Turner, Nicholas C. and de Thé, Hugues and André, Fabrice and Sotiriou, Christos and Hortobágyi, Gabriel N. and Di Leo, Angelo and Pusztai, Lajos and Santarpia, Libero (2014) TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers. Molecular Oncology, 8 (3). pp. 508-519. ISSN 1574-7891

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Abstract

Breast cancers (BC) carry a complex set of gene mutations that can influence their geneexpression and clinical behavior. We aimed to identify genes driven by the TP53 mutationstatus and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negativeBC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC an-alyses of each gene expression according to TP53 mutation status were performed. The prog-nostic value of genes with the highest AUC were assessed in a large dataset of untreated, andneoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was themost significant gene correlated with TP53 status, and the most significant prognostic markerin all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated indifferent BC cell lines. We also assessed the effects of a potent small molecule inhibitor ofMPS1, SP600125, alone and in combination with chemotherapy. Consistent with the geneexpression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reductionin 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 chemo-therapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated ki-nase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, andthat SP600125 warrant further development in future clinical trials.

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