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Proc Natl Acad Sci U S A. 2019 Feb 7. pii: 201815034. doi: 10.1073/pnas.1815034116. [Epub ahead of print]

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

Author information

1
Department of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain.
2
Instituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain.
3
Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
4
Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
5
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
6
Basque Foundation for Science (IKERBASQUE), 48013 Bilbao, Spain.
7
Molecular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
8
Department of Pharmacology, University of the Basque Country Universidad del País Vasco/Euskal Herriko Unibersitatea, 48940 Leioa, Spain.
9
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain.
10
Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain.
11
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-UAM, 28029 Madrid, Spain.
12
Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28046 Madrid, Spain.
13
Fundación MD Anderson Internacional, 28033 Madrid, Spain.
14
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.
15
Pathology Unit, Hospital 12 de Octubre, 28041 Madrid, Spain.
16
Medical Oncology Department, Hospital 12 de Octubre, 28041 Madrid, Spain.
17
School of Pharmacy, University of East Anglia, Norwich, Norfolk NR4 7TJ, United Kingdom.
18
Preclinical Research Program, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.
19
Department of Biochemistry and Molecular Biology, Institució Catalana de Recerca i Estudis Avançats, Universitat Autónoma de Barcelona, 08193 Barcelona, Spain.
20
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
21
Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.
22
Department of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain; cristina.sanchez@quim.ucm.es eduperez@ucm.es.

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.

KEYWORDS:

CB2R; HER2; breast cancer; cannabinoids; receptor heteromers

PMID:
30733293
DOI:
10.1073/pnas.1815034116

Conflict of interest statement

Conflict of interest statement: M.G. and C.S. are members of the Zelda Therapeutics Medical Advisory Board.

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