Sandra Blasco-Benito
Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer
Blasco-Benito, Sandra; Moreno, Estefan�a; Seijo-Vila, Marta; Tundidor, Isabel; Andradas, Clara; Caffarel, Mar�a M.; Caro-Villalobos, Miriam; Urig�en, Leyre; Diez-Alarcia, Rebeca; Moreno-Bueno, Gema; Hern�ndez, Luc�a; Manso, Luis; Homar-Ruano, Patricia; McCormick, Peter J.; Bibic, Lucka; Bernad�-Morales, Cristina; Arribas, Joaqu�n; Canals, Meritxell; Casad�, Vicent; Canela, Enric I.; Guzm�n, Manuel; P�rez-G�mez, Eduardo; S�nchez, Cristina
Authors
Estefan�a Moreno
Marta Seijo-Vila
Isabel Tundidor
Clara Andradas
Mar�a M. Caffarel
Miriam Caro-Villalobos
Leyre Urig�en
Rebeca Diez-Alarcia
Gema Moreno-Bueno
Luc�a Hern�ndez
Luis Manso
Patricia Homar-Ruano
Peter J. McCormick
Lucka Bibic
Cristina Bernad�-Morales
Joaqu�n Arribas
MERITXELL CANALS M.CANALS@NOTTINGHAM.AC.UK
Professor of Cellular Pharmacology
Vicent Casad�
Enric I. Canela
Manuel Guzm�n
Eduardo P�rez-G�mez
Cristina S�nchez
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.
Citation
Blasco-Benito, S., Moreno, E., Seijo-Vila, M., Tundidor, I., Andradas, C., Caffarel, M. M., …Sánchez, C. (2019). Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer. Proceedings of the National Academy of Sciences, 116(9), 3863-3872. https://doi.org/10.1073/pnas.1815034116
Journal Article Type | Article |
---|---|
Acceptance Date | Jan 3, 2019 |
Online Publication Date | Feb 7, 2019 |
Publication Date | Feb 26, 2019 |
Deposit Date | Feb 20, 2019 |
Publicly Available Date | Mar 28, 2024 |
Journal | Proceedings of the National Academy of Sciences |
Print ISSN | 0027-8424 |
Electronic ISSN | 1091-6490 |
Publisher | National Academy of Sciences |
Peer Reviewed | Peer Reviewed |
Volume | 116 |
Issue | 9 |
Pages | 3863-3872 |
DOI | https://doi.org/10.1073/pnas.1815034116 |
Keywords | Breast cancer; HER2 ; cannabinoids; Receptor heteromers; CB2R |
Public URL | https://nottingham-repository.worktribe.com/output/1572437 |
Publisher URL | https://www.pnas.org/content/early/2019/02/06/1815034116 |
Files
Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer
(2.4 Mb)
PDF
You might also like
Atypical opioid receptors: unconventional biology and therapeutic opportunities
(2021)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: digital-library-support@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search