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Role of the Microtubule-Associated Protein ATIP3 in Cell Migration and Breast Cancer Metastasis Angie Molina Delgado

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Role of the Microtubule-Associated Protein ATIP3 in Cell Migration and Breast Cancer Metastasis Angie Molina Delgado Role of the microtubule-associated protein ATIP3 in cell migration and breast cancer metastasis Angie Molina Delgado To cite this version: Angie Molina Delgado. Role of the microtubule-associated protein ATIP3 in cell migration and breast cancer metastasis. Molecular biology. Université René Descartes - Paris V, 2014. English. NNT : 2014PA05T022. tel-01068663 HAL Id: tel-01068663 https://tel.archives-ouvertes.fr/tel-01068663 Submitted on 26 Sep 2014 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. Université Paris Descartes Ecole doctorale BioSPC Thesis submitted towards fulfillment of the requirement for the degree of DOCTOR of Health & Life Sciences Specialized in Cellular and Molecular Biology Role of the microtubule-associated protein ATIP3 in cell migration and breast cancer metastasis By Angie Molina Delgado Under supervision of Dr. Clara Nahmias Thesis defense 3 September, 2014 Members of jury: Dr. Ali BADACHE Reviewer Dr. Laurence LAFANECHERE Reviewer Dr. Franck PEREZ Examiner Dr. Stéphane HONORE Examiner Dr. Clara NAHMIAS Thesis Director Table of Contents List of abbreviations ....................................................................................................................... 9 “Rôle de la protéine associée aux microtubules ATIP3 dans la migration cellulaire et la formation de métastases du cancer du sein” ................................................................................................ 11 I. INTRODUCTION ................................................................................................................... 15 1. Breast Cancer ...................................................................................................................... 17 1.1. Anatomy of the breast .................................................................................................. 17 1.2. Histology of the mammary gland .................................................................................. 17 1.2.1. Epithelial cells ....................................................................................................... 18 1.2.2. The mammary stroma ........................................................................................... 20 1.3. Breast Cancer ............................................................................................................... 21 1.3.1. Cancer generalities ............................................................................................... 21 1.3.2. Breast Cancer Epidemiology .................................................................................. 22 1.3.3. Breast Cancer Classification .................................................................................. 23 1.3.4. Breast Cancer Molecular Classification .................................................................. 25 1.3.5. Chemotherapy as a treatment for breast cancer ................................................... 31 2. Breast Cancer Metastasis ..................................................................................................... 32 2.1. The metastatic process ................................................................................................. 32 2.2. Tumor cell invasion and migration ................................................................................ 33 2.2.1. Collective Cell Migration ....................................................................................... 35 2.2.2. Single Cell Migration ............................................................................................. 37 3. Microtubule (MT) Network .................................................................................................. 38 3.1. Microtubule organization ............................................................................................. 38 3.2. Microtubule dynamics .................................................................................................. 40 3.2.1. MT dynamics in vitro ............................................................................................. 41 3.2.2. MT dynamics in vivo .............................................................................................. 44 3.3. Microtubule-targeting agents (MTAs) ........................................................................... 46 3.4. Microtubule post-translational modifications ............................................................... 47 3.5. Microtubule-regulating proteins ................................................................................... 51 1 3.5.1. Microtubule-stabilizing proteins............................................................................ 51 3.5.2. Microtubule-destabilizing proteins ........................................................................ 52 3.6. Microtubule plus-ends tracking proteins (+TIPs) ........................................................... 53 3.6.1. Structural +TIPs classification ................................................................................ 54 3.6.2. Plus-end tracking mechanisms .............................................................................. 57 3.6.3. +TIPs functions...................................................................................................... 59 3.7. End-binding protein 1 ................................................................................................... 61 3.8. Microtubules in cell migration ...................................................................................... 65 4. ATIP3 a novel therapeutic target against breast cancer ........................................................ 70 4.1. MTUS1, a candidate tumor suppressor gene ................................................................. 70 4.2. A family of ATIP proteins .............................................................................................. 72 4.3. ATIP3, A TIP top protein down-regulated in Breast Carcinoma ...................................... 75 4.4. ATIP3 is a novel Microtubule-associated protein ........................................................... 76 4.5. A functional family of Microtubule-Associated Proteins in cancer ................................. 77 II. RESULTS .............................................................................................................................. 81 ARTICLE 1: .................................................................................................................................... 83 ATIP3, a Novel Prognostic Marker of Breast Cancer Patient Survival, Limits Cancer Cell Migration and Slows Metastatic Progression by Regulating Microtubule Dynamics ...................................... 83 ARTICLE 2: .................................................................................................................................... 89 ATIP3 interacts with End Binding protein EB1 to limit its accumulation at the microtubule plus ends .................................................................................................................................................... 89 Unpublished Results .................................................................................................................... 95 1. New ATIP3 interacting partners ........................................................................................ 97 1.1. ATIP3 interacts with MCAK and regulates its localization at the MT plus-ends ........... 97 1.2. ATIP3 interacts with APC ........................................................................................... 99 2. ATIP3 role in ciliogenesis .................................................................................................101 3. MTUS1 gene mutations in breast cancer .........................................................................103 III. CONCLUSIONS ....................................................................................................................105 IV. DISCUSSION AND FUTURE DIRECTIONS ...............................................................................111 1. ATIP3 decreases MT dynamic instability ..........................................................................113 2. ATIP3 molecular complexes .............................................................................................114 3. ATIP3 is not a +TIP ...........................................................................................................116 2 4. ATIP3 impairs cell polarity and cell migration...................................................................117 5. Clinical relevance of ATIP3 ...............................................................................................118 V. REFERENCES .......................................................................................................................121 VI. ANNEXES ............................................................................................................................143 ARTICLE 3: ...................................................................................................................................145
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