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.

Descargar el artículo

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Read more

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Read more

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß after myocardial infarction

01-12-2020

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood...

Read more

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

30-10-2020

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic...

Read more

Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

01-10-2020

C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins...

Read more

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

31-08-2020

The reciprocal translocation t(12;21)(p13;q22)[ETV6/RUNX1] is the most frequent chromosomal rearrangement in pediatric B-cell acute lymphoblastic leukemia(B-ALL). Long non-coding RNAs (lncRNAs) play important roles in numerous diseases and they represent an...

Read more

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Read more

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

01-07-2020

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism...

Read more

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Read more

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Read more

Protector Members