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La regulación de ERBB2 por el receptor de estrógeno-PAX2 determina la respuesta al tamoxifeno
Antoni Hurtado1, Kelly A Holmes, Timothy R Geistlinger
1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Nature
|November 14, 2008
Resumen
Los complejos del receptor de estrógeno (ER) y el tamoxifeno reprimen directamente la transcripción ERBB2 a través de un elemento cis-regulador. La proteína PAX2 media esta represión, influyendo en la respuesta al tamoxifeno en el cáncer de mama.
Área de la Ciencia:
- Oncología Oncología.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- El cruce entre las vías del receptor de estrógenos (ER) y ERBB2 / HER-2 está implicado en el cáncer de mama.
- No se ha establecido una conexión transcripcional directa entre estas vías.
Objetivo del estudio:
- Para aclarar la regulación transcripcional directa de ERBB2 por ER y tamoxifeno.
- Identificar mediadores clave en el cruce de vías ER-ERBB2 relevantes para la respuesta al tratamiento del cáncer de mama.
Principales métodos:
- Análisis de la transcripción ERBB2 en líneas celulares humanas.
- Investigación del papel del producto genético de la caja emparejada 2 (PAX2) como mediador.
- Evaluación de la competencia entre PAX2 y AIB-1/SRC-3 para la regulación transcripcional de ERBB2.
Principales resultados:
- Los complejos de estrógeno-ER y tamoxifeno-ER reprimen directamente la transcripción de ERBB2 a través de un elemento cis-regulador específico del gen.
- PAX2 actúa como un mediador crucial para la ER y la represión ERBB2 inducida por el tamoxifeno.
- PAX2 y el coactivador de ER AIB-1/SRC-3 compiten por la regulación de ERBB2, lo que determina la respuesta al tamoxifeno.
Conclusiones:
- La interacción ER-PAX2 proporciona un vínculo mecánico entre los subtipos de cáncer de mama ER-positivo y ERBB2-positivo.
- Esta vía sugiere un mecanismo para la progresión de los tumores ER-positivos a los agresivos ERBB2-positivos.
- Los hallazgos ofrecen información sobre la resistencia endocrina en el cáncer de mama.
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