Reference

Proc Natl Acad Sci USA. 2019; 116(9) 3863-3872. https://doi.org/10.1073/pnas.181503cover source

Authors

Sandra Blasco-Benito, Estefanía Moreno, Marta Seijo-Vila, Isabel Tundidor, Clara Andradas, María M. Caffarel, Miriam Caro-Villalobos, Leyre Urigüen, Rebeca Diez-Alarcia, Gema Moreno-Bueno, Lucía Hernández, Luis Manso, Patricia Homar-Ruano, Peter J. McCormick, Lucka Bibic, Cristina Bernadó-Morales, Joaquín Arribas, Meritxell Canals, Vicent Casadó, Enric I. Canela, Manuel Guzmán, Eduardo Pérez-Gómez, and Cristina Sánchez.

Abstract

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

Description

En este trabajo describimos un nuevo mecanismo de control de la actividad del receptor HER2 (principal oncogén en el subtipo de cáncer de mama HER2-positivo): su heteromerización con el receptor de cannabinoides CB2R. Hemos observado que una expresión elevada de estos heterómeros en muestras tumorales humanas se asocia con un peor pronóstico de las pacientes. Por otro lado, hemos demostrado que la rotura de estos complejos induce respuestas antitumorales. Nuestros resultados nos permiten proponer a los heterómeros HER2-CB2R como nuevos marcadores con valor pronóstico y nuevas dianas terapéuticas para el tratamiento del cáncer de mama HER2-positivo.

 

 

mamas1

 

REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro grupo, localizado en la Facultad de CC Biológicas de la Universidad Complutense, y dirigido por Cristina Sánchez, centra su investigación en los cannabinoides, principios activos de la marihuana, y el cáncer de mama. Concretamente, queremos entender cuál es el papel del sistema endocannabinoide en la generación y progresión de esta patología y analizar el potencial de este sistema como diana de tratamientos antitumorales.

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