Publication: Importancia pronóstica, predictiva de respuesta y terapéutica de las fosfatasas MKP-1 y PP2A en el cáncer de mama humano
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2016-04-01
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Universidad Complutense de Madrid
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Abstract
El cáncer de mama es la principal causa de muerte por cáncer en mujeres en los países occidentales. La caracterización biológica de los tumores de mama de acuerdo a patrones de expresión génica mayoritarios estableció una clasificación molecular en diferentes “subtipos biológicos”, que se establecieron como estándar en el diagnóstico del cáncer de mama. Los biomarcadores clave para clasificar los tumores de mama son: el receptor de estrógenos (ER), el receptor de progesterona (PR) y el receptor del factor de crecimiento epidérmico humano 2 (HER2). La terapia principal de erradicación de esta enfermedad es la cirugía del tumor, junto a la quimioterapia adyuvante y/o neoadyuvante. El panorama actual de pronóstico y predicción de la enfermedad y su respuesta a las diferentes terapias (incluyendo terapias personalizadas) es insuficiente, sin embargo, para conseguir la erradicación completa del cáncer de mama. Se precisan, por tanto, nuevos marcadores con valor pronóstico, predictivo y terapéutico. Las proteínas fosfatasas MKP-1 y PP2A influyen en la señalización celular de las células tumorales de mama lo suficiente como para ser consideradas potenciales biomarcadores de esta enfermedad. Así, analizamos las respuestas de líneas celulares de cáncer de mama a los fármacos docetaxel y doxorrubicina en un contexto de sobreexpresión inducida de MKP-1, observando una mayor resistencia de estas células a los tratamientos. Esta sobreexpresión de MKP-1 inhibió la activación de JNK1/2, lo que incrementó la supervivencia celular frente a ambos quimioterápicos. Además, analizamos la proteína PP2A en estas mismas líneas celulares, que se encuentra inhibida por hiperfosforilación y por la expresión de las moléculas reguladoras CIP2A y SET. La activación inducida de la actividad fosfatasa de PP2A mediante el fármaco FTY720 sensibilizó a las células tumorales de mama al tratamiento con doxorrubicina. Finalmente, determinamos en biopsias de tumores de mama que la expresión de MKP-1 / p-JNK1/2, por un lado, y p-PP2A / CIP2A, por otro, correlacionaron con peor supervivencia clínica y con peor respuesta de las pacientes a la quimioterapia adyuvante y neoadyuvante. En consecuencia, nuestro trabajo demue stra el potencial de las fosfatasas MKP-1 y PP2A como marcadores en el diagnóstico clínico y en la previsión de la posible respuesta terapéutica del cáncer de mama.
Breast cance r is the most common diagnosed cancer and accounts for the majority of cancer-related deaths in European and American women. Clinically, this kind of tumor consists in a very heterogeneous disease that includes a diversity of pathological entities inside a wide clinical progression. Breast is the specific organ where this cancer is developed, which consists in a glandular system made up of lobules that can make milk and thin tubes called ducts that carry the milk from the lobules to the nipple. Most of breast tumors are adenocarcino mas or tumors composed by tumoral epithelial cells covering lobules and ducts of the breast. First stages of the disease correspond to in situ ductal or lobular carcinoma, being ductal carcinoma the most frequent breast cancer. Stage I and II tumors are usually called early breast carcinomas, while stage III and IV tumors are well known as locally advanced breast carcinomas. The most important risk factors associated with breast cancer include genetic predisposition, exposure to estrogens and ionising radiation, low parity and history of atypical hyperplasia. The diagnosis of breast cancer is based on clinical examination in combination with imaging, and confirmed by pathological assessment according to the WHO classification and the TNM staging system. Breast tumors quantification by cDNA microarrays performed by Perou CM et al achieved the molecular classification of breast carcinomas based on their gene expression signatures. Since then, the new “molecular portraits” transformed breast cancer diagnosis and were established as fundamental to provide the best prognostic and therapeutic advice. The St Gallen molecular subtype classification of breast carcinomas currently accepted distinguish among these tumor subtypes: luminal A, luminal B HER2-, luminal B HER2+, HER2+ and triple negative tumors. In order to motivate the progression in therapeutic alternatives with individualized drugs, cancer international committees are promoting the integration between mechanistic cancer research with clinical trials and the implementation of patient’s genetic and biological insights. In this context, the discovery of new biomarkers is essential to elucidate cancer molecular alterations and to classify patients for treatments. The most important biomarkers in breast cancer classification and diagnosis are estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)...
Breast cance r is the most common diagnosed cancer and accounts for the majority of cancer-related deaths in European and American women. Clinically, this kind of tumor consists in a very heterogeneous disease that includes a diversity of pathological entities inside a wide clinical progression. Breast is the specific organ where this cancer is developed, which consists in a glandular system made up of lobules that can make milk and thin tubes called ducts that carry the milk from the lobules to the nipple. Most of breast tumors are adenocarcino mas or tumors composed by tumoral epithelial cells covering lobules and ducts of the breast. First stages of the disease correspond to in situ ductal or lobular carcinoma, being ductal carcinoma the most frequent breast cancer. Stage I and II tumors are usually called early breast carcinomas, while stage III and IV tumors are well known as locally advanced breast carcinomas. The most important risk factors associated with breast cancer include genetic predisposition, exposure to estrogens and ionising radiation, low parity and history of atypical hyperplasia. The diagnosis of breast cancer is based on clinical examination in combination with imaging, and confirmed by pathological assessment according to the WHO classification and the TNM staging system. Breast tumors quantification by cDNA microarrays performed by Perou CM et al achieved the molecular classification of breast carcinomas based on their gene expression signatures. Since then, the new “molecular portraits” transformed breast cancer diagnosis and were established as fundamental to provide the best prognostic and therapeutic advice. The St Gallen molecular subtype classification of breast carcinomas currently accepted distinguish among these tumor subtypes: luminal A, luminal B HER2-, luminal B HER2+, HER2+ and triple negative tumors. In order to motivate the progression in therapeutic alternatives with individualized drugs, cancer international committees are promoting the integration between mechanistic cancer research with clinical trials and the implementation of patient’s genetic and biological insights. In this context, the discovery of new biomarkers is essential to elucidate cancer molecular alterations and to classify patients for treatments. The most important biomarkers in breast cancer classification and diagnosis are estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 01-10-2015