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A Network Biology Approach to Breast and Colorectal Cancers

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A Network Biology Approach to Breast and Colorectal Cancers A network biology approach to breast and colorectal cancers Rodrigo Arroyo Sánchez ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. 0 TESIS DOCTORAL UNIVERSITAT DE BARCELONA FACULTAT DE BIOLOGIA PROGRAMA DE DOCTORAT EN BIOMEDICINA 2014 A network biology approach to breast and colorectal cancers Estudio del cáncer de mama y colorrectal mediante biología de redes Memoria presentada por Rodrigo Arroyo Sánchez Para optar al título de doctor por la Universitat de Barcelona realizada en el Institut de Recerca Biomèdica de Barcelona. DIRECTOR DOCTORANDO Dr. Patrick Aloy Calaf Rodrigo Arroyo Sánchez 1 A mi familia y a Xey, por estar siempre ahí. 3 Los imposibles de hoy serán posibles mañana. Konstantin Tsiolkovsky (1857-1935) 5 ACKNOWLEDGMENTS M’agradaria començar aquesta secció donant les gràcies al meu director de tesi, en Patrick Aloy, per donar-me l’oportunitat de realitzar el doctorat i per haver- me format com a estudiant durant aquests anys. Gràcies per haver-me donat tots els medis per fer aquesta tesi de la millor manera i per la teva supervisió. També vull agrair a la Montse Soler tota la feina feta durant aquests anys com a directora a l’EBL. Gràcies per la teva ajuda, el teu suport i també la teva paciència i comprensió. No era fàcil fer rutllar un laboratori tan peculiar com el nostre, i cal dir que si molts hem arribat fins al final en part es gràcies a tu. Gracias a los miembros del comité de evaluación de la tesis durante estos años: Travis Stracker, Xavier Salvatella y Josep Lluís Gelpí. También quiero agradecer de antemano a Baldo Oliva, Miquel Àngel Pujana y Carles Ciudad por acceder a evaluar este trabajo, y a los miembros suplentes del tribunal: Timothy Thomson, Modesto Orozco y Ana María Rojas. Y volviendo al EBL, me faltarían páginas de agradecimientos. Comenzaré por la persona de la que creo haber aprendido más durante estos años; Guillermo. Luego vino su relevo, Nahuai, más de lo mismo, buenos compañeros y mejores personas. Moltes gràcies també a tu Victor per tota la teva ajuda, això si, no puc agarir-te l’estrés que m’han provocat les nostres xerrades futboleres . Obligada mención a parte merecen las dos chicas que me han acompañado de principio a fin en esta experiencia: gracias Chiara y Ozgen por vuestra genial compañía durante todos estos años. Y como no agradecer a los demas miembros pasados o presentes, por el genial ambiente creado entre todos: Clara, Ricart, Elisa, Kathryn, Maica, Marianela, Nuria, Eva, Jofre, Antonio, Montse, Claudio, Cristina y Raquel. Muchas gracias y mucha suerte a ti también Isabelle, estoy seguro que harás genial la faena que tienes por delante. Obligatorio acordarme también de los compañeros bioinformáticos del grupo. En especial Manu y Miquel, mis compañeros de batallas dentro y fuera del Parc, y también agradecer a Samira su ayuda y apoyo estos últimos y duros meses de tesis. Gracias también a Roland, Amelie, Andreas, Arnaud, Roberto, Lydia, Jacopo, Roger, Laura y Teresa por todos esos buenos almuerzos que hemos pasado juntos. i También quiero acordarme de todos los compañeros de los diferentes equipos de la liga de futbol del IRB, especialmente los más ilustres Nico, Rodo, Evarist, Francesc, Victor B, Radek, Camille, y los ya mencionados Manu, Chiara, Nahuai y Victor. Quiero también dar las gracias sin duda a todos los grandes amigos que tengo. Gracias a los científicos barceloneses con los que tanto congenio (Alex, Cami, Berni, Roser). Gràcies als empordanesos/esplaiencs/explaiencs per haver acollit a un merengón de la meseta (Pau, Guti, Alex, Iñaki, Miki, Martí, Jorgina, Joan, Piris, Juli, Guille, Jofre, Genís, Vice, …). Y como no, mencionar a los abulenses, muchas gracias a las familias de Navarre y de Navatal, a mi segunda familia (los R.S.O.), en especial al trío que me acompaña en todas las escapadas (Pablo, Pepe y Marcos). También dar las gracias en general a todos los amigos del pueblo, porque la semana que paso allí es la mejor del año y porque no hay nada más bonito que estar tan sumamente orgulloso de la gente y de la tierra que te vió nacer. Xey, cariño, a ti muchas gracias por tu alegría, tu compañía, tu apoyo, tus sonrisas, tu ayuda, … en definitiva gracias ser una persona tan especial. Gracias por todos los buenos momentos que hemos pasado juntos y por los que nos quedan por pasar. Y por último dar las gracias a mi familia porque conforta saber que siempre están ahí. A mi hermana, con quien tantas cosas he compartido. Gracias a mis padres por su sacrificio y por enseñarme lo que son la honestidad y la humildad, y en especial a mi madre, por todo el apoyo, cariño y dedicación que he recibido desde siempre. Esta tesis va dedicada a todos vosotros. ii TABLE OF CONTENTS Table of Contents .............................................................................. iii List of Figures ................................................................................... vii List of Tables ...................................................................................... ix Abbreviations ..................................................................................... xi Global Introduction ........................................................................... 1 I Molecular Characterization of Bc and Crc Interactomes .......................................................................... 5 1 Introduction I .......................................................................................... 7 1.1 Global Cancer Burden......................................................................... 7 1.1.1 Breast Cancer ........................................................................................ 9 1.1.2 Colorectal Cancer ............................................................................... 14 1.1.3 Advances and Challenges of Cancer Research .............................. 16 1.2 Genomic Instability ........................................................................... 18 1.2.1 DNA Repair Mechanisms ................................................................ 19 1.2.2 Genomic Instability and Cancer ...................................................... 23 1.2.3 Hereditary Breast Cancer and Genomic Instability ...................... 24 1.3 Systems and Network Biology ......................................................... 26 1.3.1 Protein-Protein Interactions ............................................................ 27 1.3.2 The Yeast Two-Hybrid Approach .................................................. 28 1.3.3 Protein-Protein Interaction (PPI) Networks ................................. 30 1.3.4 PPI Networks and Disease ............................................................... 33 2 Objectives I............................................................................................ 35 3 Results and Discussion I...................................................................... 37 iii 3.1 Expansion of Breast Cancer Interactome ...................................... 37 3.1.1 Selection of breast cancer causative and associated genes
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