Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

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 identifica...

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Detalhes bibliográficos
Autores: Blasco-Benito, Sandra, Moreno Gordaliza, María Estefanía, Seijo-Vila, Marta, Tundidor, Isabel, Andradas Arias, Clara, Caffarel, María M., Caro-Villalobos, Miriam, Urigüen, Leyre, Diez-Alarcia, Rebeca, Moreno-Bueno, Gema, Hernández, Lucia, Manso Sánchez, Luis Manuel, Homar-Ruano, Patricia, McCormick, Peter J., Bibic, Lucka, Bernadó-Morales, Cristina, Arribas, Joaquín, Canals, Meritxell, Casadó, Vicent, Canela, Enric I., Guzmán, Manuel, Pérez Gómez, Eduardo, Sánchez García, María Cristina
Tipo de documento: artigo
Data de publicação:2019
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositório:Docta Complutense
Idioma:inglês
OAI Identifier:oai:docta.ucm.es:20.500.14352/13524
Acesso em linha:https://hdl.handle.net/20.500.14352/13524
Access Level:Acceso aberto
Palavra-chave:577.1
577.2
616-006.04
Breast cancer
HER2
cannabinoids
receptor heteromers
CB2R
Oncología
Biología molecular (Biología)
Bioquímica (Biología)
3201.01 Oncología
2415 Biología Molecular
2302 Bioquímica
Descrição
Resumo: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.

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