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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

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Authors

Sandra Blasco-Benito

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

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 Aug 8, 2019
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
Contract Date Feb 20, 2019

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