TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.
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.
Research Laboratory of Pediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary; Oncogenomic Research Group, 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Balázs
B
Győrffy
Translational Research Unit, Department of Oncology, Istituto Toscano Tumori, Piazza dell'Ospedale 2, Prato 59100, Italy.
Giulia
G
Bottai
Department of Biochemistry and INSERM U944, University Rene Diderot, Paris 7, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
Jacqueline
J
Lehmann-Che
Pathobiochemistry Research Group of Hungarian Academy of Sciences, Semmelweis University, Department of Medicinal Chemistry, 1444, Bp. 8, POB 260, Hungary; Vichem Chemie Research Ltd, 1022, Herman Otto 15, Budapest, Hungary.
György
G
Kéri
Vichem Chemie Research Ltd, 1022, Herman Otto 15, Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
László
L
Orfi
Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan.
Takayuki
T
Iwamoto
Breast Cancer Translational Laboratory, Université Libre de Bruxelles, Jules Bordet Institute, Brussels, Belgium.
Christine
C
Desmedt
Division of Medical Oncology, San Raffaele - Scientific Institute, Milan, Italy.
Giampaolo
G
Bianchini
The Breakthrough Breast Cancer Research Center, Institute of Cancer Research, London, UK.
Nicholas C
NC
Turner
Department of Biochemistry and INSERM U944, University Rene Diderot, Paris 7, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
Hugues
H
de Thè
Department of Medical Oncology, Institut National de la Santé et de la Recherche Médicale Unit U981, Institut Gustave Roussy, Villejuif, France.
Fabrice
F
André
Department of Medical Oncology, Institut National de la Santé et de la Recherche Médicale Unit U981, Institut Gustave Roussy, Villejuif, France.
Christos
C
Sotiriou
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gabriel N
GN
Hortobagyi
Medical Oncology Unit Sandro Pitigliani, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
Angelo
A
Di Leo
Yale Cancer Center, New Haven, CT, USA.
Lajos
L
Pusztai
Translational Research Unit, Department of Oncology, Istituto Toscano Tumori, Piazza dell'Ospedale 2, Prato 59100, Italy. Electronic address: liberosantarpia@yahoo.it.
Libero
L
Santarpia
D000873:Anthracenes / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000873:Anthracenes; D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; C432165:pyrazolanthrone; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
Breast cancer subtypes; Chemotherapy; MPS1 protein kinase; SP600125; TP53 mutation status; Tumor relapse