TY - JOUR
T1 - Therapeutic targeting of HER2–CB 2 R heteromers in HER2-positive breast cancer
AU - Blasco-Benito, Sandra
AU - Moreno, Estefanía
AU - Seijo-Vila, Marta
AU - Tundidor, Isabel
AU - Andradas, Clara
AU - Caffarel, María M.
AU - Caro-Villalobos, Miriam
AU - Urigüen, Leyre
AU - Diez-Alarcia, Rebeca
AU - Moreno-Bueno, Gema
AU - Hernández, Lucía
AU - Manso, Luis
AU - Homar-Ruano, Patricia
AU - McCormick, Peter J.
AU - Bibic, Lucka
AU - Bernadó-Morales, Cristina
AU - Arribas, Joaquín
AU - Canals, Meritxell
AU - Casadó, Vicent
AU - Canela, Enric I.
AU - Guzmán, Manuel
AU - Pérez-Gómez, Eduardo
AU - Sánchez, Cristina
PY - 2019/2/26
Y1 - 2019/2/26
N2 - 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 CB 2 R. We show that HER2 physically interacts with CB 2 R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ 9 -tetrahydrocannabinol (THC) disrupts HER2–CB 2 R complexes by selectively binding to CB 2 R, 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 CB 2 R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB 2 R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.
AB - 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 CB 2 R. We show that HER2 physically interacts with CB 2 R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ 9 -tetrahydrocannabinol (THC) disrupts HER2–CB 2 R complexes by selectively binding to CB 2 R, 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 CB 2 R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB 2 R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.
KW - Breast cancer
KW - Cannabinoids
KW - CB R
KW - HER2
KW - Receptor heteromers
UR - http://www.scopus.com/inward/record.url?scp=85061999617&partnerID=8YFLogxK
U2 - 10.1073/pnas.1815034116
DO - 10.1073/pnas.1815034116
M3 - Article
C2 - 30733293
AN - SCOPUS:85061999617
SN - 0027-8424
VL - 116
SP - 3863
EP - 3872
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -
