title: TIPIN depletion leads to apoptosis in breast cancer cells.
abstract: Triple-negative breast cancer (TNBC) is the breast cancer subgroup with the most aggressive clinical behavior. Alternatives to conventional chemotherapy are required to improve the survival of TNBC patients. Gene-expression analyses for different breast cancer subtypes revealed significant overexpression of the Timeless-interacting protein (TIPIN), which is involved in the stability of DNA replication forks, in the highly proliferative associated TNBC samples. Immunohistochemistry analysis showed higher expression of TIPIN in the most proliferative and aggressive breast cancer subtypes including TNBC, and no TIPIN expression in healthy breast tissues. The depletion of TIPIN by RNA interference impairs the proliferation of both human breast cancer and non-tumorigenic cell lines. However, this effect may be specifically associated with apoptosis in breast cancer cells. TIPIN silencing results in higher levels of single-stranded DNA (ssDNA), indicative of replicative stress (RS), in TNBC compared to non-tumorigenic cells. Upon TIPIN depletion, the speed of DNA replication fork was significantly decreased in all BC cells. However, TIPIN-depleted TNBC cells are unable to fire additional replication origins in response to RS and therefore undergo apoptosis. TIPIN knockdown in TNBC cells decreases tumorigenicity in vitro and delays tumor growth in vivo. Our findings suggest that TIPIN is important for the maintenance of DNA replication and represents a potential treatment target for the worst prognosis associated breast cancers, such as TNBC.
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Baldeyron
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Brisson
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France; INSERM, U900, Bioinformatics, Biostatistics, Epidemiology and Computational Systems Biology of Cancer, Paris, F-75248, France; Mines ParisTech, Fontainebleau, F-77300, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tesson
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Laboratory of Preclinical Investigation, Department of Translational Research, Paris, F-75248, France.
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; CNRS, UMR 3244, Paris, F-75248, France; Université Pierre and Marie Curie Paris VI, Paris, F-75005, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Koundrioukoff
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Saliba
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; RPPA Platform, Department of Translational Research, Paris, F-75248, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.affiliation: Institut Curie, Investigative Pathology Platform, Paris, F-75248, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Martel
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France.
authors.forename: Mengliang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Unité de Recherche en Génomique Végétale, INRA-CNRS-Université d'Evry Val d'Essonne, Evry, F-91057, France.
authors.forename: Guillem
authors.initials: G
authors.lastname: Rigaill
authors.affiliation: Institut Curie, Investigative Pathology Platform, Paris, F-75248, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.affiliation: Institut Curie, Investigative Pathology Platform, Paris, F-75248, France.
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Platform of Molecular Biology Facilities, Department of Translational Research, Paris, F-75248, France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Laboratory of Preclinical Investigation, Department of Translational Research, Paris, F-75248, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; CNRS, UMR 3244, Paris, F-75248, France; Université Pierre and Marie Curie Paris VI, Paris, F-75005, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatisse
authors.affiliation: Institut de Recherches SERVIER, Pôle Innovation Thérapeutique Oncologie, Croissy-sur-Seine, F-78290, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.affiliation: Institut de Recherches SERVIER, Pôle Innovation Thérapeutique Oncologie, Croissy-sur-Seine, F-78290, France.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.affiliation: Institut de Recherches SERVIER, Pôle Innovation Thérapeutique Oncologie, Croissy-sur-Seine, F-78290, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Institut de Recherches SERVIER, Pôle Innovation Thérapeutique Oncologie, Croissy-sur-Seine, F-78290, France.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Tucker
authors.affiliation: Institut Curie, Centre de Recherche, Paris, F-75248, France; Breast Cancer Biology Group, Department of Translational Research, Paris, F-75248, France. Electronic address: thierry.dubois@curie.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C516227:Tipin protein, human
keywords: Apoptosis; Basal-like; Replicative stress; TIPIN; Therapeutic target; Triple-negative breast cancer