Publication: Implicación de nuevas moléculas de la vía de señalización de Ras en el cáncer de mama
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2018-09-18
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Universidad Complutense de Madrid
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Abstract
El cáncer de mama es el tipo de tumor más frecuente en la población femenina de todo el mundo y, aunque su tasa de mortalidad no es la más elevada, es la causa más frecuente de muerte por cáncer en las mujeres. Aunque tradicionalmente se ha utilizado la expresión de los receptores hormonales y del receptor HER2 para clasificar los tumores de mama, diferentes estudios genómicos han definido recientemente varios subtipos moleculares intrínsecos de cáncer de mama que están asociados con diferentes alteraciones moleculares y distintos parámetros clínicos, incluyendo la respuesta terapéutica. El cáncer de mama humano es un grupo heterogéneo de enfermedades y su desarrollo está desencadenado por una amplia variedad de mecanismos moleculares que varían entre individuos. Por esta razón, los genes cuyas alteraciones dan lugar a la tumorigénesis mamaria son sólo parcialmente conocidos. Nosotros hemos empleado un modelo de ratón basado en el sistema de transposición “sleeping beauty” (una herramienta eficaz para la identificación de genes involucrados en cáncer) para identificar genes implicados en el desarrollo del cáncer de mama. Así, hemos identificado a Nf1, Rasa1 (dos genes Ras-GAP) y a Eras (un miembro de la familia Ras raramente expresado), como genes candidatos implicados directamente en tumorigénesis mamaria. Aunque los genes de la familia Ras son algunos de los mutados más frecuentemente en los tumores humanos, menos del 1% de los tumores de mama tienen mutaciones en los genes Ras clásicos (H-, N-, K-RAS). A pesar de esto, la vía de Ras está significativamente activada en algunos tumores de mama humanos, especialmente en los tumores triple negativos. Ya que la vía de señalización de Ras también puede ser activada por otros miembros de la familia Ras o por la inactivación de moléculas que limitan la actividad de Ras, como las proteínas Ras-GAP, algunas alteraciones de estos genes podrían ser responsables de la activación de la vía de Ras en los tumores mamarios...
Breast cancer is by far the most frequent tumor type in the female population worldwide and although its mortality rate is not the highest, it is the most frequent cause of cancer death in women. Although hormone and HER2 receptors status have been traditionally used to classify breast tumors, recent genomic studies have defined several breast cancer intrinsic molecular subtypes, which are associated with different molecular alterations and distinct clinical outcome including therapeutic response. Breast cancer is a heterogeneous group of diseases and its development is triggered by a large variety of molecular mechanisms, which are variable among different individuals. For this reason, the driver genes whose alterations lead to breast tumorigenesis are only partially known. We have used a mouse model based on the sleeping beauty transposon system (a powerful tool for the identification of cancer driver genes) to identify genes involved in breast cancer development. Following this approach, we identified Nf1, Rasa1 (two Ras-GAP genes) and Eras (a usually silent member of the Ras family), as candidate genes implicated in mammary tumorigenesis. Although Ras genes are among the most frequently mutated genes in human cancer, less than 1% of breast cancers carry mutations in classical Ras genes (H-, N-, K-RAS). In spite of this observation, the Ras pathway is significantly activated in some human breast tumors, especially in the triplenegative type. As Ras signaling may be activated also by activating mutations of other members of the Ras family or, notably, by inactivation of molecules that limit Ras activity, such as Ras-GAP proteins, alterations of these genes could be responsible of Ras activation in breast cancer...
Breast cancer is by far the most frequent tumor type in the female population worldwide and although its mortality rate is not the highest, it is the most frequent cause of cancer death in women. Although hormone and HER2 receptors status have been traditionally used to classify breast tumors, recent genomic studies have defined several breast cancer intrinsic molecular subtypes, which are associated with different molecular alterations and distinct clinical outcome including therapeutic response. Breast cancer is a heterogeneous group of diseases and its development is triggered by a large variety of molecular mechanisms, which are variable among different individuals. For this reason, the driver genes whose alterations lead to breast tumorigenesis are only partially known. We have used a mouse model based on the sleeping beauty transposon system (a powerful tool for the identification of cancer driver genes) to identify genes involved in breast cancer development. Following this approach, we identified Nf1, Rasa1 (two Ras-GAP genes) and Eras (a usually silent member of the Ras family), as candidate genes implicated in mammary tumorigenesis. Although Ras genes are among the most frequently mutated genes in human cancer, less than 1% of breast cancers carry mutations in classical Ras genes (H-, N-, K-RAS). In spite of this observation, the Ras pathway is significantly activated in some human breast tumors, especially in the triplenegative type. As Ras signaling may be activated also by activating mutations of other members of the Ras family or, notably, by inactivation of molecules that limit Ras activity, such as Ras-GAP proteins, alterations of these genes could be responsible of Ras activation in breast cancer...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular, leída el 21 de Marzo de 2017