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1. Mise à jour 2021 des recommandations du GEFPICS pour l’évaluation du statut HER2 dans les cancers infiltrants du sein en France

Author

Bruno Poulet, Alexander Valent, Jean-Pierre Ghnassia, Gaëtan MacGrogan, Lounes Djerroudi, Véronique Becette, Aurélie Maran-Gonzalez, Emmanuelle Charafe-Jauffret, Olivia Abramovici, Marie-Mélanie Dauplat, Cécile Blanc-Fournier, Yves Marie Robin, Agnès Leroux, Isabelle Treilleux, Frédérique Penault-Llorca, Elisabeth Russ, Paul Delrée, Eva Brabencova, Magali Lacroix-Triki, Pascal Roger, Juliette Haudebourg, Martine Antoine, Anca Berghian, Véronique Verriele, Patrick Michenet, Raphaëlle Duprez-Paumier, Marie-Pierre Chenard, Clémence Fleury, Anne Vincent-Salomon, Camille Franchet, Laurent Arnould, Lucie Tixier, Pour le Gefpics, Marie-Christine Mathieu, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER

Subjects
Clinical Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], medicine.disease, 3. Good health, Pathology and Forensic Medicine, Clinical trial, 03 medical and health sciences, Status assessment, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Family medicine, Medicine, Personalized medicine, skin and connective tissue diseases, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

Published
2021

2. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016

Author

Laurence Vanlemmens, Marc Debled, Magali Lacroix-Triki, Christelle Levy, David Pérol, Lionel Uwer, Elise Deluche, Véronique Diéras, Thierry Petit, Veronique Lorgis, Thomas Bachelot, Simone Mathoulin-Pélissier, Anne Patsouris, Mathieu Robain, Jean Marc Ferrero, Marie Ange Mouret-Reynier, C. Courtinard, Florence Dalenc, Etienne Brain, Alison Antoine, C. Lefeuvre-Plesse, Marianne Leheurteur, Christelle Jouannaud, William Jacot, Anthony Gonçalves, Suzette Delaloge, Audrey Lardy-Cleaud, CHU Limoges, Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Medical Oncology Department, Salah Azaiz Institute, Department of Medical Oncology [Saint-Cloud], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Claudius Regaud, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Plateforme de génétique moléculaire des cancers d'Aquitaine, Centre Paul Strauss, CRLCC Paul Strauss, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département de Biologie et de Pathologie, Department of Biostatistics, Institut Curie [Paris], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université de Lille-UNICANCER

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Real life, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Medical economics, Internal medicine, HER2, Epidemiology, Overall survival, medicine, skin and connective tissue diseases, Observational database, Subtypes, business.industry, Cancer, medicine.disease, Metastatic breast cancer, Confidence interval, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, business
Abstract

Aim Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). Methods Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. Results The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p Conclusions The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. Database registration clinicaltrials.gov Identifier NCT032753.

Published
2020

3. Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Author

Theodoros I. Roumeliotis, Jérôme Moreaux, Julia Gilhodes, Julien Mazieres, Marie-Jeanne Pillaire, Hélène Tourrière, Valérie Bergoglio, Julien N Bianco, Jean-Sébastien Hoffmann, Yea-Lih Lin, Amélie Lusque, Anne-Lyne Schmitz, Jyoti S. Choudhary, Magali Lacroix-Triki, Philippe Pasero, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, CHU Toulouse [Toulouse], Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), The institute of cancer research [London], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Larose, Catherine, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
0301 basic medicine, Timeless, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Adenocarcinoma of Lung, Breast Neoplasms, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, 02 engineering and technology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Genomic Instability, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Stress, Physiological, Cell Line, Tumor, medicine, Humans, Tumor growth, lcsh:Science, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Replication stress, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, General Chemistry, HCT116 Cells, 021001 nanoscience & nanotechnology, medicine.disease, Primary tumor, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cell culture, Checkpoint Kinase 1, Cancer cell, MCF-7 Cells, lcsh:Q, Cancer development, biological phenomena, cell phenomena, and immunity, Colorectal Neoplasms, 0210 nano-technology, DNA Damage, HeLa Cells
Abstract

Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner., Oncogene-induced replication stress (RS) promotes cancer development. Here, the authors report that cancer cells adapt to oncogene-induced RS by overexpressing downstream components of ATR-CHK1 pathway, Claspin and Timeless, which have protective role at the replication forks independent of their checkpoint function.

Published
2019

4. Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy

Author

Magali Lacroix-Triki, Clara Nahmias, Jean-Yves Pierga, Elisabetta Marangoni, Marie-Eglantine Dujaric, Patricia de Cremoux, Nicolas Servant, Bernard Asselain, Fabrice Andre, Cynthia Seiler, Monica Arnedos, Sylvie Rodrigues-Ferreira, Clarisse Monchecourt, Sophie Chateau-Joubert, Hadia Moindjie, Anne Nehlig, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Institut Curie [Paris], Université Paris sciences et lettres (PSL), BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), MINES ParisTech - École nationale supérieure des mines de Paris, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, 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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de biologie et pathologie médicales [Gustave Roussy], Département de médecine oncologique [Gustave Roussy], Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Hôpital René HUGUENIN (Saint-Cloud), École nationale vétérinaire - Alfort (ENVA), Mines Paris - PSL (École nationale supérieure des mines de Paris), and NAHMIAS, Clara

Subjects
0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Aneuploidy, Video microscopy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, chemistry.chemical_compound, 0302 clinical medicine, Multicenter Studies as Topic, ATIP3, predictive biomarker, Randomized Controlled Trials as Topic, education.field_of_study, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, DNA, Neoplasm, Biological Sciences, Neoadjuvant Therapy, 3. Good health, Neoplasm Proteins, [SDV] Life Sciences [q-bio], MTUS1, Paclitaxel, 030220 oncology & carcinogenesis, Heterografts, RNA Interference, Taxoids, Population, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Spindle Apparatus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Time-Lapse Imaging, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Neoplasm Invasiveness, education, Mitosis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cytokinesis, multipolar spindle, Chemotherapy, business.industry, Gene Expression Profiling, Tumor Suppressor Proteins, medicine.disease, Antineoplastic Agents, Phytogenic, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, taxanes, Cancer research, business, Multipolar spindles, Neoplasm Transplantation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.

Published
2019

5. Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis

Author

Thierry Dubois, Anne Vincent-Salomon, Anne Nehlig, Véronique Scott, Sarah Nasr, Fabrice Andre, Sylvie Rodrigues-Ferreira, Magali Lacroix-Triki, Barbara Pistilli, Ingrid Garberis, Clarisse Monchecourt, Suzette Delaloge, Laetitia Fuhrmann, Philippe Vielh, Clara Nahmias, NAHMIAS, Clara, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inovarion, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Curie [Paris], and Département de biologie et pathologie médicales [Gustave Roussy]

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Population, Prognosis, Gene Expression, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Malignancy, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, Biomarkers combination, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Diagnosis, Biomarkers, Tumor, Medicine, Humans, education, MAPRE1, education.field_of_study, Tissue microarray, business.industry, Tumor Suppressor Proteins, medicine.disease, Survival Analysis, 3. Good health, MTUS1, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Biomarker (medicine), Immunohistochemistry, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Neoplasm Grading, business, Microtubule-Associated Proteins
Abstract

International audience; Purpose: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis.Methods: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies.Results: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results.Conclusions: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.

Published
2019

6. Fuzzy logic selection as a new reliable tool to identify molecular grade signatures in breast cancer – the INNODIAG study

Author

Carine Valle, Tatiana Kempowsky-Hamon, Jean-Marie François, Gilles Favre, Delphine Labourdette, Sophie Lamarre, Magali Lacroix-Triki, Marie-Véronique Le Lann, Loubna Mhamdi, Lidwine Trouilh, Lyamine Hedjazi, Thomas Filleron, Florence Dalenc, Véronique Anton-Leberre, Laurence Roger, Équipe DIagnostic, Supervision et COnduite (LAAS-DISCO), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dendris SAS, Département d'oncologie médicale, Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), National Research Agency (Agence National pour la Recherche), 'BIOTECHNOLOGIES' program [ANR 2010 BIOT 004 06], 'pole de competitivite' Cancer-Bio-Sante from Midi Pyrenees, France, ANR, Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Équipe DIagnostic, Supervision et COnduite ( LAAS-DISCO ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés ( LISBP ), Institut National de la Recherche Agronomique ( INRA ) -Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Claudius Regaud, Department of Radiation Oncology and Medical Physics, Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, [SDV]Life Sciences [q-bio], Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, Breast cancer, Databases, Genetic, Genetics(clinical), Precision Medicine, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Gene signatures, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Gene Expression Regulation, Neoplastic, Molecular grade, Female, DNA microarray, Algorithms, Research Article, medicine.medical_specialty, Decision Making, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fuzzy logic, Sensitivity and Specificity, [ INFO.INFO-LG ] Computer Science [cs]/Machine Learning [cs.LG], Text mining, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Genetics, Humans, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ INFO.INFO-AI ] Computer Science [cs]/Artificial Intelligence [cs.AI], business.industry, Gene Expression Profiling, Computational Biology, Reproducibility of Results, Gene signature, Precision medicine, medicine.disease, Gene expression profiling, Personalized medicine, Neoplasm Recurrence, Local, business
Abstract

Background Personalized medicine has become a priority in breast cancer patient management. In addition to the routinely used clinicopathological characteristics, clinicians will have to face an increasing amount of data derived from tumor molecular profiling. The aims of this study were to develop a new gene selection method based on a fuzzy logic selection and classification algorithm, and to validate the gene signatures obtained on breast cancer patient cohorts. Methods We analyzed data from four published gene expression datasets for breast carcinomas. We identified the best discriminating genes by comparing molecular expression profiles between histologic grade 1 and 3 tumors for each of the training datasets. The most pertinent probes were selected and used to define fuzzy molecular grade 1-like (good prognosis) and fuzzy molecular grade 3-like (poor prognosis) profiles. To evaluate the prognostic performance of the fuzzy grade signatures in breast cancer tumors, a Kaplan-Meier analysis was conducted to compare the relapse-free survival deduced from histologic grade and fuzzy molecular grade classification. Results We applied the fuzzy logic selection on breast cancer databases and obtained four new gene signatures. Analysis in the training public sets showed good performance of these gene signatures for grade (sensitivity from 90% to 95%, specificity 67% to 93%). To validate these gene signatures, we designed probes on custom microarrays and tested them on 150 invasive breast carcinomas. Good performance was obtained with an error rate of less than 10%. For one gene signature, among 74 histologic grade 3 and 18 grade 1 tumors, 88 cases (96%) were correctly assigned. Interestingly histologic grade 2 tumors (n = 58) were split in these two molecular grade categories. Conclusion We confirmed the use of fuzzy logic selection as a new tool to identify gene signatures with good reliability and increased classification power. This method based on artificial intelligence algorithms was successfully applied to breast cancers molecular grade classification allowing histologic grade 2 classification into grade 1 and grade 2 like to improve patients prognosis. It opens the way to further development for identification of new biomarker combinations in other applications such as prediction of treatment response. Electronic supplementary material The online version of this article (doi:10.1186/s12920-015-0077-1) contains supplementary material, which is available to authorized users.

Published
2015

7. Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial

Author

Céline Charon-Barra, Marc Spielmann, Pierre Fumoleau, Henri Roché, Laurent Arnould, Déwi Vernerey, Mario Campone, Jérôme Lemonnier, Christel Mesleard, Magali Lacroix-Triki, Séverine Guiu, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CRLCC René Gauducheau, Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Claudius Regaud, and R&D Unicancer [Paris]

Subjects
Adult, Hepatocyte Nuclear Factor 3-alpha, Cancer Research, Estrogen receptor, Gene Expression, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, molecular apocrine tumors, Breast cancer, androgen receptor, Antineoplastic Combined Chemotherapy Protocols, Odds Ratio, Medicine, Humans, Triple-negative breast cancer, Neoplasm Staging, business.industry, Apocrine, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, 3. Good health, Tumor Burden, Androgen receptor, Oncology, Receptors, Androgen, Cancer research, triple-negative breast cancer, Female, FOXA1, Neoplasm Grading, business
Abstract

International audience; Aim: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation. Materials & methods: Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC). Results: Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis. Conclusion: TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.

Published
2015

8. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Author

Aicha Goubar, Julien Adam, Joanna Cyrta, Kariman Chaba, Mireia Niso-Santano, Valentina La Sorsa, Laurence Zitvogel, Christina Pfirschke, Guido Kroemer, Gilles Uzé, Oliver Kepp, Magali Lacroix-Triki, Francesca Urbani, Antonella Sistigu, Elisa E. Baracco, Suzette Delaloge, Sylvain Ladoire, David Enot, Camilla Engblom, Marco Bianchi, Laurent Arnould, Virginie Quidville, Mauro Delorenzi, Enrico Proietti, Melvyn T. Chow, Laetitia Aymeric, Fabrice Andre, Giovanna Ziccheddu, Joachim L. Schultze, Alexander M.M. Eggermont, Thomas Tüting, Laetitia Fend, Mark J. Smyth, Catarina Remédios, Takahiro Yamazaki, Robert D. Schreiber, Laura Bracci, Erika Vacchelli, Rosa Conforti, Ilio Vitale, Paola Sestili, Mikael J. Pittet, Marie Charlotte Dessoliers, Filippo Belardelli, Vichnou Poirier-Colame, Frédérique Penault-Llorca, Jean Philippe Spano, Lajos Pusztai, Xavier Préville, Dalil Hannani, Yuting Ma, National Cancer Institute Regina Elena [Rome, Italy], Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Département de biologie et pathologie médicales [Gustave Roussy], Apoptose, cancer et immunité (U848), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Life and Medical Sciences Institute for Genomics and Immunoregulation, Universität Bonn = University of Bonn, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER-UNICANCER, Harvard Medical School [Boston] (HMS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology and Neurosciences, Université Paris-Sud - Paris 11 (UP11), Sistigu, A, Yamazaki, T, Vacchelli, E, Chaba, K, Enot, Dp, Adam, J, Vitale, I, Goubar, A, Baracco, Ee, Remédios, C, Fend, L, Hannani, D, Aymeric, L, Ma, Y, Niso Santano, M, Kepp, O, Schultze, Jl, Tüting, T, Belardelli, F, Bracci, L, La Sorsa, V, Ziccheddu, G, Sestili, P, Urbani, F, Delorenzi, M, Lacroix Triki, M, Quidville, V, Conforti, R, Spano, Jp, Pusztai, L, Poirier Colame, V, Delaloge, S, Penault Llorca, F, Ladoire, S, Arnould, L, Cyrta, J, Dessoliers, Mc, Eggermont, A, Bianchi, MARCO EMILIO, Pittet, M, Engblom, C, Pfirschke, C, Préville, X, Uzè, G, Schreiber, Rd, Chow, Mt, Smyth, Mj, Proietti, E, André, F, Kroemer, G, Zitvogel, L., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), University of Bonn, Istituto Superiore di Sanità, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Superiore di Sanita', and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Myxovirus Resistance Proteins, Messenger, Receptor, Interferon alpha-beta, Inbred C57BL, chemotherapy, Interferon alpha-beta, Mice, Interferon, Receptors, Anthracyclines, Neoplasm Metastasis, RIG-I, Pattern recognition receptor, Adaptor Proteins, General Medicine, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Pattern Recognition, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunocompetence, medicine.drug, Receptor, Signal Transduction, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pattern Recognition, Settore BIO/09, General Biochemistry, Genetics and Molecular Biology, Paracrine signalling, Immune system, medicine, CXCL10, Animals, Humans, cancer, RNA, Messenger, Autocrine signalling, Neoplastic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Toll-Like Receptor 3, Mice, Inbred C57BL, Vesicular Transport, Chemokine CXCL10, Adaptor Proteins, Vesicular Transport, Gene Expression Regulation, Doxorubicin, Immunology, TLR3, RNA
Abstract

International audience; The immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. npg

Published
2014

9. Recommandations du GEFPICS concernant la phase pré-analytique pour l’évaluation de HER2 et des récepteurs hormonaux dans le cancer du sein : mise à jour 2014

Author

Juliette Haudebourg, Christian Garbar, Jean-Pierre Ghnassia, Myriam Marcy, Pascal Genin, Martine Antoine, Marie-Christine Mathieu, Marie-Eve Fondrevelle, Viviana Fridman, Aurélie Maran-Gonzalez, Pascal Roger, Alexander Valent, Frédérique Penault-Llorca, Anne Vincent-Salomon, Laurent Arnould, Emmanuelle Charafe-Jauffret, Mojgan Devouassoux, Christine Sagan, Delphine Loussouarn, Paul Delrée, Isabelle Treilleux, Eva Brabencova, Bruno Poulet, Patrick Michenet, Véronique Becette, Marie-Pierre Chenard, Marie-Mélanie Dauplat, Magali Lacroix-Triki, Véronique Verriele, Catherine Bor, Sophie Laberge-Le Couteulx, Maryse Fiche, Martine Trassard, Gaëtan MacGrogan, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
0303 health sciences, Recommandations, [SDV]Life Sciences [q-bio], Immunohistochimie, Guidelines, Fixation, Immunohistochemistry, 3. Good health, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, breast cancer, Biomarqueur, 030220 oncology & carcinogenesis, HER2, biomarker, Fixative, Cancer du sein, 030304 developmental biology
Abstract

International audience; Les tumeurs fixées et incluses en paraffine sont quotidiennement utilisées pour l’évaluation des biomarqueurs nécessaires au traitement des patientes atteintes d’un cancer du sein invasif. Les nouvelles recommandations internationales sur la phase pré-analytique ont été récemment revues, confirmant l’importance de la prise en charge optimale des prélèvements pour garantir des tests d’immunohistochimie ou d’hybridation in situ de qualité, quel que soit le biomarqueur envisagé. Incluant les procédés de fixation et de préparation des tissus, toutes les procédures pré-analytiques doivent être validées, standardisées et tracées. Elles nécessitent la collaboration et la formation de toutes les personnes impliquées dans le circuit du prélèvement, du préleveur jusqu’au technicien de pathologie et au pathologiste en passant par l’infirmière, ou le coursier. La prise en charge initiale optimale des pièces et une fixation de qualité sont des étapes majeures à maîtriser dans la phase pré-analytique. Cette mise à jour des recommandations du groupe d’étude des facteurs pronostiques immunohistochimiques dans le cancer du sein (GEFPICS) détaille et commente les différentes étapes pré-analytiques. L’observation de ces règles de bonne pratique, l’utilisation rigoureuse de témoins internes et externes et la participation régulière à des programmes d’assurance qualité sont autant de garanties pour une évaluation correcte et pérenne des biomarqueurs oncothéranostiques., Summary Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS’ update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.

Published
2014

10. RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor

Author

Elise Meunier, Isabelle Lajoie-Mazenc, Claudine Marty, Magali Lacroix-Triki, Laura Keller, Emilie Malissein, Thomas Filleron, Sophie F. Doisneau-Sixou, Gilles Favre, Claire Medale-Giamarchi, Bettina Couderc, Florence Dalenc, Yann Berge, BMC, Ed., Faculté des Sciences Pharmaceutiques, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie de Toulouse-Purpan (INSERM U563 - CNRS UMR1037), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut Claudius Regaud-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de lutte contre le cancer (CLCC)-Centre National de la Recherche Scientifique (CNRS), Individualisation des traitements des cancers ovariens (ITCO), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Biologie et de Pathologie, Institut Claudius Regaud, Tumorbiologischen Labor, Klinikum der Ludwig-Maximilians-Universität, This work was supported by the National Institute of Cancer, Canceropole Grand Sud-Ouest, Fondation RITC (C Silvagni), INSERM, Claudius Regaud Institute, University of Toulouse (UPS) and the French Ministry of Research (MRES)., Centre National de la Recherche Scientifique (CNRS)-Centre de lutte contre le cancer (CLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut Claudius Regaud, and Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
medicine.drug_class, RHOB, Estrogen receptor, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Progesterone receptor, RhoB GTP-Binding Protein, medicine, Humans, RNA, Messenger, rhoB GTP-Binding Protein, Estrogen receptor beta, 030304 developmental biology, Cell Proliferation, Regulation of gene expression, Medicine(all), 0303 health sciences, Estrogen Receptor alpha, 3. Good health, Gene Expression Regulation, Neoplastic, Estrogen, Tissue Array Analysis, 030220 oncology & carcinogenesis, Cancer research, Female, Receptors, Progesterone, Estrogen receptor alpha, Research Article
Abstract

International audience; ABSTRACT: INTRODUCTION: RhoB has been reported to exert positive and negative effects on cancer pathophysiology but an understanding of its role in breast cancer remains incomplete. Analysis of data from the Oncomine database showed a positive correlation between RhoB expression and positivity for both the Estrogen Receptor alpha (ERalpha) and the Progesterone Receptor (PR). METHODS: This finding was validated by our analysis of a tissue microarray constructed from a cohort of 113 patients and then investigated in human cell models. RESULTS: We found that RhoB expression in tissue was strongly correlated with ER and PR expression and inversely correlated with tumor grade, tumor size and count of mitosis. In human breast cancer cell lines, RhoB attenuation was associated with reduced expression of both ERalpha and PR, whereas elevation of RhoB was found to be associated with ERalpha overexpression. Mechanistic investigations suggested that RhoB modulates ERalpha expression controlling both its protein and mRNA levels, and that RhoB modulates PR expression by accentuating the recruitment of ERalpha and other major co-regulators to the promoter of PR gene. A major consequence of RhoB modulation was that RhoB differentially regulated the proliferation of breast cancer cell lines. Interestingly, we documented crosstalk between RhoB and ERalpha, with estrogen treatment leading to RhoB activation. CONCLUSIONS: Taken together, our findings offer evidence that in human breast cancer RhoB acts as a positive function to promote expression of ERalpha and PR in a manner correlated with cell proliferation.

Published
2013

11. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase.: PTPL1 inhibits Src activation and tumor aggressiveness

Author

Murielle Glondu-Lassis, Dany Chalbos, Dora Knani, Magali Lacroix-Triki, Carole Puech, Mathilde Dromard, Gilles Freiss, Philippe Nirdé, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Departement de Pathologie, Institut Claudius Regaud,Toulouse, Fédération Nationale des Centres de Lutte contre le Cancer, and This work was supported by the 'Institut National de la Santé et de la Recherche Médicale', the 'Ligue Nationale Contre le Cancer-comité des Pyrénées Orientales', and by the 'Institut National du Cancer' (grant number 0611-3D1019-34/valo, 0610-3D1616-118PL2006). M. Dromard and M. Glondu-Lassis were supported by grants from 'Ligue Nationale Contre le Cancer' and the 'Institut National du Cancer'

Subjects
MESH: Signal Transduction, Cancer Research, MESH: Lymphatic Metastasis, Protein Tyrosine Phosphatase, Non-Receptor Type 13, Fluorescent Antibody Technique, Protein tyrosine phosphatase, Signal transduction, Metastasis, Immunoenzyme Techniques, Mice, Protein tyrosine phosphatase N13, 0302 clinical medicine, Cell Movement, MESH: RNA, Small Interfering, MESH: Animals, Tumor suppressor gene, Phosphorylation, RNA, Small Interfering, MESH: Cell Movement, MESH: Fluorescent Antibody Technique, 0303 health sciences, 3. Good health, src-Family Kinases, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Female, Breast disease, MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 13, MESH: Tissue Array Analysis, Proto-oncogene tyrosine-protein kinase Src, Src, MESH: Cell Line, Tumor, Blotting, Western, Mice, Nude, breast cancer aggressiveness, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, MESH: Cell Adhesion, 03 medical and health sciences, Cell Line, Tumor, MESH: Cell Proliferation, medicine, Cell Adhesion, MESH: Mice, Nude, Animals, Humans, MESH: Blotting, Western, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Immunoenzyme Techniques, MESH: Mice, 030304 developmental biology, Cell Proliferation, MESH: Humans, MESH: Phosphorylation, Cancer, MESH: Neoplasm Invasiveness, medicine.disease, PTPN13, MESH: src-Family Kinases, Tumor progression, Tissue Array Analysis, Cancer research, MESH: Female, MESH: Breast Neoplasms
Abstract

The protein tyrosine phosphatase PTPL1/PTPN13, the activity of which is decreased through allelic loss, promoter methylation, or somatic mutations in some tumors, has been proposed as a tumor suppressor gene. Moreover, our recent clinical study identified PTPL1 expression level as an independent prognostic indicator of a favorable outcome for patients with breast cancer. However, how PTPL1 can affect tumor aggressiveness has not been characterized. Here, we first show that PTPL1 expression, assessed by immunohistochemistry, is decreased in breast cancer and metastasis specimens compared with nonmalignant tissues. Second, to evaluate whether PTPL1 plays a critical role in breast cancer progression, RNA interference experiments were performed in poorly tumorigenic MCF-7 breast cancer cells. PTPL1 inhibition drastically increased tumor growth in athymic mice and also enhanced several parameters associated with tumor progression, including cell proliferation on extracellular matrix components and cell invasion. Furthermore, the inhibition of Src kinase expression drastically blocked the effects of PTPL1 silencing on cell growth. In PTPL1 knockdown cells, the phosphorylation of Src on tyrosine 419 is increased, leading to the activation of its downstream substrates Fak and p130cas. Finally, substrate-trapping experiments revealed that Src tyrosine 419 is a direct target of the phosphatase. Thus, by identification of PTPL1 as the first phosphatase able to inhibit Src through direct dephosphorylation in intact cells, we presently describe a new mechanism by which PTPL1 inhibits breast tumor aggressiveness. Cancer Res; 70(12); 5116–26. ©2010 AACR.

Published
2010

12. Cortactin gene amplification and expression in breast cancer: a chromogenic in situ hybridisation and immunohistochemical study

Author

Jorge S. Reis-Filho, Paul M. Wilkerson, Maryou B K Lambros, Magali Lacroix-Triki, Daniel Wetterskog, Konstantin J. Dedes, Felipe C. Geyer, Maria-Angeles Lopez-Garcia, Radost Vatcheva, Rachael Natrajan, Kay Savage, Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, Hospital Universitario Virgen del Rocío [Sevilla], and Institut Claudius Regaud

Subjects
Cancer Research, Time Factors, CTTN, Breast Neoplasms, Kaplan-Meier Estimate, Biology, Disease-Free Survival, CCND1, Breast cancer, Predictive Value of Tests, Gene duplication, London, medicine, Biomarkers, Tumor, Humans, Cyclin D1, CISH, In Situ Hybridization, Mastectomy, Neoplasm Staging, Retrospective Studies, Tissue microarray, Chromosomes, Human, Pair 11, 11q13 amplification, Gene Amplification, Cancer, Amplicon, medicine.disease, Molecular biology, Immunohistochemistry, Up-Regulation, Treatment Outcome, Oncology, Chromogenic Compounds, Chemotherapy, Adjuvant, Tissue Array Analysis, Female, Breast disease, Cortactin, Digoxigenin, Chromogenic in situ hybridisation, Comparative genomic hybridization
Abstract

Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the ‘driver’ of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification. The aims of this study are to define whether CTTN is consistently co-amplified with the main core of the 11q13 amplicon, whether it is consistently overexpressed when amplified and to determine correlations between CTTN amplification and overexpression with clinicopathological features of breast cancers and survival of breast cancer patients. CTTN and CCND1 chromogenic in situ hybridisation (CISH) probes and a validated monoclonal antibody against CTTN were applied to a tissue microarray of a cohort of breast cancers from patients treated with anthracycline-based chemotherapy. CTTN and CCND1 amplifications were found in 12.3 and 12.4% of cases, respectively. All cases harbouring CTTN amplification also displayed CCND1 amplification. High expression of CTTN was found in 10.8% of cases and was associated with CTTN amplification, expression of ‘basal’ markers and topoisomerase IIα. Exploratory subgroup analysis of tumours devoid of 11q13 amplification revealed that high expression of CTTN in the absence of CTTN gene amplification was associated with lymph node negative disease, lack of hormone receptors and FOXA1, expression of ‘basal’ markers, high Ki-67 indices, p53 nuclear expression, and basal-like and triple negative phenotypes. CTTN expression and CTTN gene amplification were not associated with disease-, metastasis-free and overall survival. In conclusion, CTTN is consistently co-amplified with CCND1 and expressed at higher levels in breast cancers harbouring 11q13 amplification, suggesting that CTTN may also constitute one of the drivers of this amplicon. CTTN expression is not associated with the outcome of breast cancer patients treated with anthracycline-based chemotherapy.

Published
2010

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