Journal Article

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, Bianchini, Giampaolo, Turner, Nicholas C., Sotiriou, Christos, Pusztai, Lajos, Őrfi, László, Santarpia, Libero, Hortobagyi, Gabriel N., André, Fabrice, de Thè, Hugues, Lehmann-Che, Jacqueline, Desmedt, Christine, Di Leo, Angelo, Iwamoto, Takayuki, Kéri, György, Bottai, Giulia

2014

Overview

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. •TP53 status is associated with two sets of genes in ER+ and ER- breast tumors.•Genes associated with TP53 status were correlated to RFS in ER+ patients.•MPS1 was the most significant gene associated with TP53 status and poor prognosis.•MPS1 inhibition affected cell viability and apoptosis in TP53 mutated cells.•Targeting MPS1 by SP600125 sensitizes TP53 mutated cells to chemotherapy.

• Publisher: Elsevier B.V,Wiley,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: [SDV.CAN]Life Sciences [q-bio]/Cancer / Anthracenes / Anthracenes - pharmacology / Apoptosis / Breast / Breast - drug effects / Breast - metabolism / Breast - pathology / Breast -- drug effects -- metabolism -- pathology / Breast cancer / Breast cancer subtypes / Breast Neoplasms / Breast Neoplasms - diagnosis / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Breast Neoplasms -- diagnosis -- drug therapy -- genetics -- pathology / Cancer therapies / Cancérologie / Cell cycle / Cell Cycle Proteins / Cell Cycle Proteins - antagonists & inhibitors / Cell Cycle Proteins - genetics / Cell Cycle Proteins -- antagonists & inhibitors -- genetics / Cell death / Cell Line / Cell Line, Tumor / Cell Survival / Cell viability / Chemotherapy / Clinical trials / Cytotoxicity / Datasets / Drugs / Estrogen receptors / Female / Gene expression / Genes / Genes, p53 / Genomes / Humans / Kinases / Local -- diagnosis -- drug therapy -- genetics -- pathology / Medical prognosis / Menopause / MPS1 protein kinase / Mutation / Médecine pathologie humaine / Neoplasm Recurrence / Neoplasm Recurrence, Local / Neoplasm Recurrence, Local - diagnosis / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / onkológia / p53 / p53 Protein / Patients / Prognosis / Protein Serine-Threonine Kinases / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases -- antagonists & inhibitors -- genetics / Protein-Tyrosine Kinases / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases -- antagonists & inhibitors -- genetics / RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok / siRNA / SP600125 / Studies / Survival Analysis / Taxanes / Therapeutic applications / TP53 mutation status / Tumor / Tumor relapse / Tumor Suppressor Protein p53 / Tumor Suppressor Protein p53 - genetics / tumorok / Tumors