title: TTK/hMPS1 is an attractive therapeutic target for triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
authors.affiliation: Institut Curie, Research Center, Paris, France ; Breast Cancer Biology Group, Department of Translational Research, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Maire
authors.forename: Céline
authors.initials: C
authors.lastname: Baldeyron
authors.forename: Marion
authors.initials: M
authors.lastname: Richardson
authors.forename: Bruno
authors.initials: B
authors.lastname: Tesson
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.forename: Eléonore
authors.initials: E
authors.lastname: Gravier
authors.forename: Bérengère
authors.initials: B
authors.lastname: Marty-Prouvost
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.forename: Guillem
authors.initials: G
authors.lastname: Rigaill
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dumont
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Tucker
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018572:Disease-Free Survival; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D058990:Molecular Targeted Therapy; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality
chemical_list: D018797:Cell Cycle Proteins; D020543:Proteome; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7