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1. Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.

Author

Fariba Némati, Catherine de Montrion, Guillaume Lang, Laurence Kraus-Berthier, Guillaume Carita, Xavier Sastre-Garau, Aurélie Berniard, David Vallerand, Olivier Geneste, Ludmilla de Plater, Alain Pierré, Brian Lockhart, Laurence Desjardins, Sophie Piperno-Neumann, Stéphane Depil, and Didier Decaudin

Subjects
Medicine, Science
Abstract

PurposeUveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines.Experimental designFour well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC).ResultsS44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration.ConclusionThe novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

Published
2014
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2. TTK/hMPS1 is an attractive therapeutic target for triple-negative breast cancer.

Author

Virginie Maire, Céline Baldeyron, Marion Richardson, Bruno Tesson, Anne Vincent-Salomon, Eléonore Gravier, Bérengère Marty-Prouvost, Leanne De Koning, Guillem Rigaill, Aurélie Dumont, David Gentien, Emmanuel Barillot, Sergio Roman-Roman, Stéphane Depil, Francisco Cruzalegui, Alain Pierré, Gordon C Tucker, and Thierry Dubois

Subjects
Medicine, Science
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.

Published
2013
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14. Event-based Information Extraction for the biomedical domain: the Caderige project

Author

Alphonse, Erick, Aubin, Sophie, Bessières, Philippe, Bisson, Gilles, Hamon, Thierry, Lagarrigue, Sandrine, Nazarenko, Adeline, Manine, Alain-Pierre, Nédellec, Claire, Vetah, Mohamed Ould Abdel, Poibeau, Thierry, and Weissenbacher, Davy

Subjects
Computer Science - Artificial Intelligence, Computer Science - Information Retrieval, H.3.1
Abstract

This paper gives an overview of the Caderige project. This project involves teams from different areas (biology, machine learning, natural language processing) in order to develop high-level analysis tools for extracting structured information from biological bibliographical databases, especially Medline. The paper gives an overview of the approach and compares it to the state of the art.

Published
2006

16. Supplementary Table S1 from S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

Author

Stéphane Depil, Francisco H. Cruzalegui, John A. Hickman, Alain Pierré, Jean-Claude Ortuno, Alex Cordi, Jean A. Boutin, Brian P. Lockhart, Paolo M. Comoglio, Anne Jacquet-Bescond, Valérie Cattan, François Bouzom, Georges Da Violante, Gilles Ferry, Stéphane Léonce, Alain Bruno, Imre Fejes, Carine Saunier, Céline J. Bossard, and Mike F. Burbridge

Abstract

Pharmacokinetic parameters of S49076 administered orally to female balb/c nu/nu mice

Published
2023
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17. Data from S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

Author

Stéphane Depil, Francisco H. Cruzalegui, John A. Hickman, Alain Pierré, Jean-Claude Ortuno, Alex Cordi, Jean A. Boutin, Brian P. Lockhart, Paolo M. Comoglio, Anne Jacquet-Bescond, Valérie Cattan, François Bouzom, Georges Da Violante, Gilles Ferry, Stéphane Léonce, Alain Bruno, Imre Fejes, Carine Saunier, Céline J. Bossard, and Mike F. Burbridge

Abstract

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Published
2023
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18. Supplementary Figure S1 from S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

Author

Stéphane Depil, Francisco H. Cruzalegui, John A. Hickman, Alain Pierré, Jean-Claude Ortuno, Alex Cordi, Jean A. Boutin, Brian P. Lockhart, Paolo M. Comoglio, Anne Jacquet-Bescond, Valérie Cattan, François Bouzom, Georges Da Violante, Gilles Ferry, Stéphane Léonce, Alain Bruno, Imre Fejes, Carine Saunier, Céline J. Bossard, and Mike F. Burbridge

Abstract

Western blot detection of total and phosphorylated MET, AXL, FGFR1/2/3 and phosphorylated FRS2 in cell lines and tumor xenografts used in the study

Published
2023
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19. Supplementary Figure Legends from S49076 Is a Novel Kinase Inhibitor of MET, AXL, and FGFR with Strong Preclinical Activity Alone and in Association with Bevacizumab

Author

Stéphane Depil, Francisco H. Cruzalegui, John A. Hickman, Alain Pierré, Jean-Claude Ortuno, Alex Cordi, Jean A. Boutin, Brian P. Lockhart, Paolo M. Comoglio, Anne Jacquet-Bescond, Valérie Cattan, François Bouzom, Georges Da Violante, Gilles Ferry, Stéphane Léonce, Alain Bruno, Imre Fejes, Carine Saunier, Céline J. Bossard, and Mike F. Burbridge

Abstract

Supplementary Figure Legends

Published
2023
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20. Supplementary Figure 1 from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 156K, Histopathological characterization of the tumor samples.

Published
2023
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21. Supplementary Figure 4 from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 923K, Comparison of gene expression between primary tumor sample, early and late xenograft sample.

Published
2023
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22. Supplementary Tables 1 - 4 from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 129K, Table S1: Description of sequenced exons. Table S2: tumor growth observed in the first engraftment. Table S3: Tumor samples for which development of metastasis has been observed after an engraftment into the cecum. Table S4: Ontology analysis of gene differentially expressed between patient tumors and xenografts.

Published
2023
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23. CCR Translation for This Article from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

CCR Translation for This Article from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Published
2023
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24. Data from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients. Clin Cancer Res; 18(19); 5314–28. ©2012 AACR.

Published
2023
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25. Supplementary Figure 2 from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 241K, Frequency of abnormalities detected by aCGH among all samples tested across the genome.

Published
2023
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26. Supplementary Figure 3 from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 67K, Hierarchical clustering of 82 tumors based on Chromosomal abnormalities analyzed by 244k aCGH.

Published
2023
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27. Supplementary Figure Legend from Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer

Author

Cyril Berthet, Olivier Duchamp, Sergio Roman-Roman, Patricia Vrignaud, Grégoire Prévost, Brigitte Demers, Loreley Calvet, Guillaume Lardier, Manoel Nunes, Hany Soliman, Hugues De Thé, Alain Pierré, Alain Bruno, Philippe Dessen, Bastien Job, Virginie Dangles-Marie, Patrick Gonin, Emmanuel Pham, Loïc Morgand, Denis Lantuas, Louis-Bastien Weiswald, Peggy Dartigues, Fariba Nemati, Ludovic Bigot, Sophie Landron, Pascale Mariani, Diane Goéré, Marc Pocard, Ludovic Lacroix, Ana Merino-Trigo, and Sylvia Julien

Abstract

PDF file, 72K.

Published
2023
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28. Supplementary Methods from Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

Author

Thierry Dubois, Gordon C. Tucker, Stéphane Depil, Francisco Cruzalegui, Alain Pierré, Sergio Roman-Roman, Didier Decaudin, Elisabetta Marangoni, Emmanuel Barillot, Aurélie Dumont, David Gentien, Guillaume Lang, Leanne De Koning, Bérengère Marty-Prouvost, Eléonore Gravier, Guillem Rigaill, Bruno Tesson, Anne Vincent-Salomon, Marion Richardson, Fariba Némati, and Virginie Maire

Abstract

PDF file - 122K

Published
2023
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29. Supplementary Figure Legend from Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

Author

Thierry Dubois, Gordon C. Tucker, Stéphane Depil, Francisco Cruzalegui, Alain Pierré, Sergio Roman-Roman, Didier Decaudin, Elisabetta Marangoni, Emmanuel Barillot, Aurélie Dumont, David Gentien, Guillaume Lang, Leanne De Koning, Bérengère Marty-Prouvost, Eléonore Gravier, Guillem Rigaill, Bruno Tesson, Anne Vincent-Salomon, Marion Richardson, Fariba Némati, and Virginie Maire

Abstract

PDF file - 66K

Published
2023
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30. Extraction of Genic Interactions with the Recursive Logical Theory of an Ontology

Author

Manine, Alain-Pierre, Alphonse, Erick, Bessières, Philippe, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, and Gelbukh, Alexander, editor

Published
2010
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32. Evaluating Language Models Within a Predictive Framework: An Analysis of Ranking Distributions

Author

Alain, Pierre, Boëffard, Olivier, Barbot, Nelly, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Dough, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Carbonell, Jaime G., editor, Siekmann, Jörg, editor, Sojka, Petr, editor, Kopeček, Ivan, editor, and Pala, Karel, editor

Published
2006
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46. Le poids du vice : Roman

Author

Tavares, Alain Pierre and Tavares, Alain Pierre

Subjects
Sexual abuse victims--Fiction, Senegalese fiction (French), Incest victims--Fiction, Young women--Violence against--Senegal--Fiction, Marital violence--Fiction, Husband and wife--Fiction
Abstract

Le roman raconte le lourd fardeau de la jeune Marianne; chassée de chez elle après sa grossesse par un père pervers, séparée de son enfant, traumatisée par le naufrage du bateau'Le Joola', Marianne est aussi une femme trompée par son mari... Et pour comble, elle découvre que son ex-petit ami est son demi-frère...

Published
2018

47. Dual-task versus single-task gait rehabilitation after stroke: the protocol of the cognitive-motor synergy multicenter, randomized, controlled superiority trial (SYNCOMOT)

Author

Sophie Tasseel-Ponche, Martine Roussel, Monica N. Toba, Thibaud Sader, Vincent Barbier, Arnaud Delafontaine, Jonathan Meynier, Carl Picard, Jean-Marc Constans, Alexis Schnitzler, Olivier Godefroy, and Alain Pierre Yelnik

Subjects
Stroke, Rehabilitation, Multitask, Gait, Cognitive-motor interference, Protocol, Medicine (General), R5-920
Abstract

Abstract Background Gait disorders and cognitive impairments are prime causes of disability and institutionalization after stroke. We hypothesized that relative to single-task gait rehabilitation (ST GR), cognitive-motor dual-task (DT) GR initiated at the subacute stage would be associated with greater improvements in ST and DT gait, balance, and cognitive performance, personal autonomy, disability, and quality of life in the short, medium and long terms after stroke. Methods This multicenter (n=12), two-arm, parallel-group, randomized (1:1), controlled clinical study is a superiority trial. With p

Published
2023
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48. TIPIN depletion leads to apoptosis in breast cancer cells

Author

Elie Saliba, Stéphane Koundrioukoff, Gordon C. Tucker, David Gentien, Leanne De Koning, Sergio Roman-Roman, Thierry Dubois, Stéphane Depil, Didier Meseure, Didier Decaudin, André Nicolas, Mengliang Ye, Michelle Debatisse, Guillem Rigaill, Amélie Brisson, Alain Pierré, Francisco Cruzalegui, Bruno Tesson, Céline Baldeyron, Fariba Nemati, Elise Martel, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Université Pierre et Marie Curie - Paris 6 (UPMC), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), SERVIER, Mines Paris - PSL (École nationale supérieure des mines de Paris), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and ProdInra, Migration

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], TIPIN, Estrogen receptor, Cell Cycle Proteins, Triple Negative Breast Neoplasms, Apoptosis, Mice, 0302 clinical medicine, Tumor Cells, Cultured, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, RNA, Small Interfering, Research Articles, Triple-negative breast cancer, 0303 health sciences, Nuclear Proteins, General Medicine, Replicative stress, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Female, DNA Replication, Therapeutic target, Mice, Nude, Biology, 03 medical and health sciences, Replication fork protection complex, Breast cancer, Genetics, medicine, Animals, Humans, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Replication protein A, 030304 developmental biology, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Molecular biology, Proliferating cell nuclear antigen, Tissue Array Analysis, Cancer research, biology.protein, Basal-like, Carrier Proteins, Gene Deletion
Abstract

International audience; 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.

Published
2015
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50. mépapasonlà

Author

Alain Pierre Boisvert and Alain Pierre Boisvert

Abstract

« — Peux-tu me décrire, mon hibou, ce que tu avais dessiné dans ta classe? poursuit Ricky, encore un peu secoué par le tintouin amplifié de notre crocodile. — Une grande plage avec des jeux et la mer et le soleil et des oiseaux et des châteaux de sable et des ballons et des parasols et des coquillages et des écrevisses et des bateaux à voile… retrace-t-il avec la main droite pour bien rapporter la position de chaque élément sur une feuille imaginaire. — Est-ce qu'il y avait aussi des gens sur ton dessin? — Oui. Moi, les Cormier et vous deux sur vos chaises longues. J'avais écrit… Il recommence à mugir de plus belle avant de compléter sa phrase. Il court dans son sac chercher le dessin et reviens, toujours en larmes. C'est alors que l'on comprend mieux l'infâme outrage de la pauvre Madame Lucie… Elle a daigné biffer en rouge “mépapasonlà” pour écrire en dessous : “Mes papas sont là.”… à même l'œuvre d'art! La pauvre enseignante se voit ainsi vouée à l'enfer pour l'éternité. »

Published
2016

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