Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy
| Autor: | 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 |
|---|---|
| Přispěvatelé: | 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), NAHMIAS, Clara |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (47), pp.23691-23697. ⟨10.1073/pnas.1910824116⟩ Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (47), pp.23691-23697. ⟨10.1073/pnas.1910824116⟩ |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|