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Improving Breast Cancer Sensitivity to Paclitaxel by Increasing Aneuploidy Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy Sylvie Rodrigues-Ferreira, Anne Nehlig, Hadia Moindjie, Clarisse Monchecourt, Cynthia Seiler, Elisabetta Marangoni, Sophie Chateau-Joubert, Marie-Eglantine Dujaric, Nicolas Servant, Bernard Asselain, et al. To cite this version: Sylvie Rodrigues-Ferreira, Anne Nehlig, Hadia Moindjie, Clarisse Monchecourt, Cynthia Seiler, et al.. Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy. 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. hal-02411561 HAL Id: hal-02411561 https://hal-univ-tlse2.archives-ouvertes.fr/hal-02411561 Submitted on 24 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 69 2 Improving breast cancer sensitivity to paclitaxel by 70 3 71 4 increasing aneuploidy 72 5 73 6 74 Sylvie Rodrigues-Ferreira1,2, Anne Nehlig1, Hadia Moindjie1, Clarisse Monchecourt1, Cynthia Seiler1, Elisabetta 7 75 Marangoni3, Sophie Chateau-Joubert4, Marie-Eglantine Dujaric5, Nicolas Servant6, Bernard Asselain5, Patricia de 8 7 8 8 9 1,8 1* 76 9 Cremoux , Magali Lacroix-Triki , Monica Arnedos , Jean-Yves Pierga , Fabrice André , and Clara Nahmias 77 10 1. INSERM U981, LabEx LERMIT, Université Paris Sud, Gustave Roussy Research Center, Department of Molecular Medicine, 94800 Villejuif, France. 2. Present 78 11 address : Inovarion SAS, 75013 Paris, France. 3. Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, PSL Research 79 12 University, Paris, France. 4. BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, Maisons Alfort, France. 5. Institut Curie, PSL Research University, Mines Paris 80 13 Tech, Bioinformatics and Computational Systems Biology of Cancer, Paris, France. 6. Institut Curie, Unit of Biometry, PSL Research University, INSERM U900, 81 Paris, France. 7. APHP Molecular Oncology Unit, Hôpital Saint Louis, Paris Diderot University, France. 8. Department of Medical Oncology, Gustave Roussy, 14 94800 Villejuif, France. 9. Medical Oncology Department, Institut Curie, Saint Cloud, Paris, France ; Université Paris Descartes, Sorbonne Paris Cite, Paris, 82 15 France 83 16 84 17 Submitted to Proceedings of the National Academy of Sciences of the United States of America 85 18 Predictive biomarkers for tumor response to neoadjuvant lowing preoperative chemotherapy remains low, reaching 15-20% 86 19 chemotherapy are needed in breast cancer. This study investigates in the whole population and 30-40% in ER-negative tumors (7,8). 87 20 the predictive value of 280 genes encoding proteins that Considering the rapidly growing area of personalized medicine, 88 21 regulate microtubule assembly and function. By analyzing the identification of efficient molecular markers that can predict 89 22 three independent multicenter randomized cohorts of breast sensitivity to chemotherapy is crucial to select the patients who 90 23 cancer patients, we identified 17 genes that are differentially may benefit from therapy, thereby avoiding unnecessary treat- 91 24 regulated in tumors achieving pathological complete response ment and associated toxicities for those who remain resistant (9). 92 25 (pCR) to neoadjuvant chemotherapy. We focused on MTUS1gene, The most used regimens in the neoadjuvant setting of breast 93 26 whose major product ATIP3Submission is a microtubule-associated protein cancer patients includePDF taxanes and anthracyclines, which com- 94 27 down-regulated in aggressive breast tumors. We show here bination is associated with improved outcome compared to an- 95 28 that low levels of ATIP3 are associated with increased pCR rate, thracyclines alone (3). Taxanes (paclitaxel and docetaxel) are 96 29 pointing to ATIP3 as a new predictive biomarker of breast tumor microtubule-targeting agents that bind and stabilize microtubules 97 30 chemosensitivity. Using preclinical models of patient-derived (MT), inducing mitotic arrest and apoptosis (10, 11). At clinically 98 31 xenografts and 3D models of breast cancer cell lines, we show relevant concentrations of the nanomolar range, these drugs 99 32 that low ATIP3 levels sensitize tumors to the effects of taxanes suppress MT dynamic instability (11-13) and behave as mitotic 100 33 but not DNA-damaging agents. ATIP3 silencing improves the pro- poisons that target the mitotic spindle during mitosis, inducing 101 34 apoptotic effects of paclitaxel and induces mitotic abnormalities, multipolar spindles and centrosomal abnormalities (13). The 102 35 including centrosome amplification and multipolar spindle assembly and dynamics of the mitotic spindle are tightly regu- 103 36 formation, which results in chromosome missegregation leading lated by a number of MT-associated proteins (MAP) and mitotic 104 37 to aneuploidy. As shown by time-lapse videomicroscopy, ATIP3 kinases (14, 15), suggesting that alterations of MAP expression 105 38 depletion exacerbates cytokinesis failure and mitotic death and/or function in breast tumors may regulate their sensitivity 106 39 induced by low doses of paclitaxel. Our results favor a mechanism to taxane-based chemotherapy. Gene expression studies indeed 107 40 by which the combination of ATIP3 deficiency and paclitaxel identified the MAP tau protein as a predictive biomarker whose 108 41 treatment induces excessive aneuploidy, which in turn results down-regulation is associated with increased pCR rate in breast 109 42 in elevated cell death. Together, these studies highlight ATIP3 cancer patients (16-21), underlining the interest of studying MT- 110 43 as a new important regulator of mitotic integrity and a useful regulating proteins as new predictors of chemotherapy efficacy. 111 44 predictive biomarker for a population of chemoresistant breast 112 45 cancer patients. 113 46 Significance 114 47 MTUS1 j predictive biomarker j texanes j multipolar spindle j aneu- 115 48 ploidy Low levels of ATIP3 in breast tumors are associated with 116 49 increased response to neoadjuvant chemotherapy and ATIP3 117 50 silencing in breast cancer cells potentiates the effects of pacli- 118 Introduction 51 taxel, highlighting the importance of this predictive biomarker 119 Breast cancer is a leading cause of cancer death among women to select breast cancer patients who are sensitive to taxane- 52 based chemotherapy. ATIP3 depletion promotes mitotic ab- 120 53 worldwide. Neo-adjuvant chemotherapy, administered before normalities including centrosome amplification and multipolar 121 54 surgery, represents an option for a number of breast cancer pa- spindle formation, which is a source of chromosome segre- 122 55 tients (1). Pre-operative chemotherapy decreases primary tumor gation errors and aneuploidy. Excessive aneuploidy in ATIP3- 123 burden, thus facilitating breast conservation (2, 3), and admin- deficient cells treated with low doses of paclitaxel results in 56 massive cell death. 124 57 istration of chemotherapy on naïve tumors prior to surgery also 125 58 provides the opportunity to rapidly measure tumor response and Reserved for Publication Footnotes 126 59 identify breast cancer patients that may gain advantage from the 127 60 treatment. The achievement of pathological complete response 128 61 (pCR), characterized by complete eradication of all invasive 129 62 cancer cells from the breast and axillary lymph nodes, is often 130 63 considered as a surrogate endpoint for cancer-free survival after 131 64 neoadjuvant setting, especially in aggressive triple-negative breast 132 65 tumors (4,5). Clinical parameters, such as estrogen receptor- 133 66 negative status, high histological grade and high proliferative sta- 134 67 tus have been associated with greater sensitivity to chemotherapy 135 68 (5,6). However, the proportion of patients who achieve a pCR fol- 136 www.pnas.org --- --- PNAS Issue Date Volume Issue Number 1--?? 137 205 138 206 139 207 140 208 141 209 142 210 143 211 144 212 145 213 146 Table 1. MT-regulating genes differentially expressed in 214 147 chemosensitive breast tumors 215 148 216 149 Gene Gene Name Process 217 150 Symbol 218 151 219 152 ASPM Abnormal spindle MT minus-end binding, 220 153 microtubule assembly spindle organization 221 154 AURKB Aurora kinase B Ser/Thr protein kinase, 222 155 spindle organization 223 156 GTSE1 G2 and S phase-expressed 1 MT plus-end binding, 224 157 spindle organization, cell 225 158 migration 226 159 KIF11 Kinesin family member 11 MT molecular motor 227 160 activity, spindle 228 161 organization 229 162 SubmissionKIF14 Kinesin PDF family member 14 MT molecular motor 230 163 activity 231 KIF15 Kinesin family member 15 MT molecular motor 164 232 activity 165 KIF18B Kinesin family member 18B MT depolymerizing 233 166 activity, spindle 234 167 organization 235 168 KIF20A Kinesin family member 20A MT molecular motor 236 169 activity 237 170 KIF2C Kinesin family member 2C MT depolymerizing 238 171 Fig. 1. A-Venn diagram of the number of differentially expressed genes be- activity, spindle 239
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