{"id":100156,"date":"2010-08-04T00:00:00","date_gmt":"2010-08-04T00:00:00","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/cellular-and-molecular-effects-of-hsp90-inhibition-by-17-aag-in-sporadic-and-hereditary-breast-cancer\/"},"modified":"2010-08-04T00:00:00","modified_gmt":"2010-08-04T00:00:00","slug":"cellular-and-molecular-effects-of-hsp90-inhibition-by-17-aag-in-sporadic-and-hereditary-breast-cancer","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/biologia-molecular\/cellular-and-molecular-effects-of-hsp90-inhibition-by-17-aag-in-sporadic-and-hereditary-breast-cancer\/","title":{"rendered":"Cellular and molecular effects of hsp90 inhibition by 17-aag in sporadic and hereditary breast cancer"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Magdalena Bogumila Zajac <\/strong><\/h2>\n<p>Cellular and molecular effects of hsp90 inhibition by 17-aag in sporadic and hereditary breast cancer heat shock protein 90 (hsp 90) es una chaperona implicada en la estabilizaci\u00f3n, plegamiento correcto, maduraci\u00f3n y ensamblaje de prote\u00ednas, denominadas prote\u00ednas clientes, las cuales en muchos casos regulan la supervivencia de las c\u00e9lulas tumorales. En trabajos previos se ha descrito una correlaci\u00f3n entre una alta expresi\u00f3n de hsp90 y una menor supervivencia en c\u00e1ncer de mama, lo que sugiere que hsp90 podr\u00eda ser una diana terap\u00e9utica interesante a investigar en el tratamiento de este tipo de tumores. en la primera parte de nuestro estudio hemos examinado la respuesta de una serie de l\u00edneas celulares de c\u00e1ncer de mama tanto brca1-normal como brca1-mutado a un inhibidor de hsp90, el 17-allyloamino-17-demetoxi-geldanamicina (17-aag). Tras el tratamiento con este f\u00e1rmaco, las c\u00e9lulas sensibles se paran en la fase g2\/m de ciclo celular, y dependiendo del estatus de brca1 entran o no en una mitosis aberrante. En las c\u00e9lulas con brca1 mutado no se produce una parada en g2 antes de entrar en mitosis, lo que resulta en la formaci\u00f3n de alteraciones como c\u00e9lulas micronucleadas, segregaci\u00f3n aberrante de cromosomas, formaci\u00f3n an\u00f3mala de microt\u00fabulos, o centrosomas m\u00faltiples, lo que conlleva la muerte celular mediante cat\u00e1strofe mit\u00f3tica. las c\u00e9lulas con brca1 normal mueren predominantemente por apoptosis. Nuestros resultados muestran que tras el tratamiento con 17-aag, brca1 interviene en el control de la transici\u00f3n g2\/m principalmente a trav\u00e9s de chek1. por otro lado, dado que la inhibici\u00f3n de hsp90 conlleva la degradaci\u00f3n de un gran n\u00famero de prote\u00ednas clientes involucradas en numerosas v\u00edas de se\u00f1alizaci\u00f3n celulares, hemos realizado un an\u00e1lisis global de expresi\u00f3n g\u00e9nica mediante microarrays, para identificar genes y rutas importantes para la respuesta a este tratamiento en c\u00e1ncer de mama. En este estudio hemos podido identificar una firma gen\u00e9tica de respuesta al 17-aag compuesta por 35 genes, as\u00ed como hemos identificado dos isoformas de hsp70 (hspa1l y hspa2) como nuevos biomarcadores de respuesta en tumores de mama. Adem\u00e1s hemos encontrado genes y rutas de se\u00f1alizaci\u00f3n diferencialmente expresados entre c\u00e9lulas sensibles y resistentes al tratamiento. Hemos encontrado tanto mediante an\u00e1lisis in silico como mediante ensayos funcionales, que la v\u00eda de se\u00f1alizaci\u00f3n de nf\u00c2\u00bfb se encuentra significativamente activada en c\u00e9lulas resistentes tras el tratamiento, indicando que este v\u00eda puede ser importante para dise\u00f1ar nuevas terapias combinadas que permitan evitar la resistencias a este f\u00e1rmaco. finalmente hemos estudiado mediante inmunohistoqu\u00edmica la expresi\u00f3n de determinados marcadores de respuesta y resistencia a 17-aag, previamente obtenidos en los estudios de expresi\u00f3n, y analizado su correlaci\u00f3n con otros marcadores fenot\u00edpicos com\u00fanmente establecidos para caracterizar los tumores de mama<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Cellular and molecular effects of hsp90 inhibition by 17-aag in sporadic and hereditary breast cancer<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Cellular and molecular effects of hsp90 inhibition by 17-aag in sporadic and hereditary breast cancer <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Magdalena Bogumila Zajac <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Aut\u00f3noma de Madrid<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 08\/04\/2010<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Beatriz Martinez Delgado<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: jose Fernandez piqueras <\/li>\n<li>amancio Carnero moya (vocal)<\/li>\n<li>Ana Osorio cabrero (vocal)<\/li>\n<li>gloria Ribas despuig (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Magdalena Bogumila Zajac Cellular and molecular effects of hsp90 inhibition by 17-aag in sporadic and hereditary breast 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