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

Sandra Blasco-Benito, Estefanía Moreno, Marta Seijo-Vila, Isabel Tundidor, Clara Andradas, María M. Caffarel, Miriam Caro-Villalobos, Leyre Urigüen, Rebeca Diez-Alarcia, Gema Moreno-Bueno, Lucía Hernández, Luis Manso, Patricia Homar-Ruano, Peter J. McCormick, Lucka Bibic, Cristina Bernadó-Morales, Joaquín Arribas, Meritxell Canals, Vicent Casadó, Enric I. Canela, Manuel Guzmán, Eduardo Pérez-Gómez, and Cristina Sánchez
PNAS published ahead of print February 7, 2019 https://doi.org/10.1073/pnas.1815034116
Sandra Blasco-Benito
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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Estefanía Moreno
cDepartment of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain;dInstitute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain;eCentro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
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Marta Seijo-Vila
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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Isabel Tundidor
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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Clara Andradas
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;
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María M. Caffarel
fBasque Foundation for Science (IKERBASQUE), 48013 Bilbao, Spain;gMolecular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain;
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  • ORCID record for María M. Caffarel
Miriam Caro-Villalobos
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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Leyre Urigüen
hDepartment of Pharmacology, University of the Basque Country Universidad del País Vasco/Euskal Herriko Unibersitatea, 48940 Leioa, Spain;iCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain;
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Rebeca Diez-Alarcia
hDepartment of Pharmacology, University of the Basque Country Universidad del País Vasco/Euskal Herriko Unibersitatea, 48940 Leioa, Spain;iCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain;
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Gema Moreno-Bueno
jDepartment of Biochemistry, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain;kInstituto de Investigaciones Biomédicas “Alberto Sols,” Consejo Superior de Investigaciones Científicas-UAM, 28029 Madrid, Spain;lInstituto de Investigación Hospital Universitario La Paz (IdiPAZ), 28046 Madrid, Spain;mFundación MD Anderson Internacional, 28033 Madrid, Spain;nCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain;
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Lucía Hernández
bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;oPathology Unit, Hospital 12 de Octubre, 28041 Madrid, Spain;
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Luis Manso
bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;pMedical Oncology Department, Hospital 12 de Octubre, 28041 Madrid, Spain;
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Patricia Homar-Ruano
cDepartment of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain;dInstitute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain;eCentro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
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Peter J. McCormick
qSchool of Pharmacy, University of East Anglia, Norwich, Norfolk NR4 7TJ, United Kingdom;
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Lucka Bibic
nCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain;
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Cristina Bernadó-Morales
nCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain;rPreclinical Research Program, Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain;
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Joaquín Arribas
nCentro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain;rPreclinical Research Program, Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain;sDepartment of Biochemistry and Molecular Biology, Institució Catalana de Recerca i Estudis Avançats, Universitat Autónoma de Barcelona, 08193 Barcelona, Spain;
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Meritxell Canals
tMonash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;
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Vicent Casadó
cDepartment of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain;dInstitute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain;eCentro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
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Enric I. Canela
cDepartment of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain;dInstitute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain;eCentro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;
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Manuel Guzmán
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;eCentro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;uInstituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain
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Eduardo Pérez-Gómez
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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  • For correspondence: cristina.sanchez@quim.ucm.eseduperez@ucm.es
Cristina Sánchez
aDepartment of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;bInstituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain;
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  • For correspondence: cristina.sanchez@quim.ucm.eseduperez@ucm.es
  1. Edited by William J. Muller, McGill University, Montreal, QC, Canada, and accepted by Editorial Board Member Peter K. Vogt January 3, 2019 (received for review September 3, 2018)

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Significance

There is a subtype of breast cancer characterized by the overexpression of the oncogene HER2. Although most patients with this diagnosis benefit from HER2-targeted treatments, some do not respond to these therapies and others develop resistance with time. New tools are therefore warranted for the treatment of this patient population, and for early identification of those individuals at a higher risk of developing innate or acquired resistance to current treatments. Here, we show that HER2 forms heteromer complexes with the cannabinoid receptor CB2R, the expression of these structures correlates with poor patient prognosis, and their disruption promotes antitumor responses. Collectively, our results support HER2–CB2R heteromers as new therapeutic targets and prognostic tools in HER2+ breast cancer.

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.

  • breast cancer
  • HER2
  • cannabinoids
  • receptor heteromers
  • CB2R

Footnotes

  • ↵1Present address: Area of Chronic and Severe Diseases, Telethon Kids Institute, Nedlands, WA 6009, Australia.

  • ↵2Present address: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom.

  • ↵3To whom correspondence may be addressed. Email: cristina.sanchez{at}quim.ucm.es or eduperez{at}ucm.es.
  • Author contributions: M.G., E.P.-G., and C.S. designed research; S.B.-B., E.M., M.S.-V., I.T., C.A., M.M.C., M.C.-V., L.U., R.D.-A., L.H., L.M., P.H.-R., P.J.M., L.B., M.C., and E.P.-G. performed research; G.M.-B., C.B.-M., and J.A. contributed new reagents/analytic tools; V.C., E.I.C., and C.S. analyzed data; and S.B.-B. and C.S. wrote the paper.

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

  • This article is a PNAS Direct Submission. W.J.M. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815034116/-/DCSupplemental.

Published under the PNAS license.

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Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer
Sandra Blasco-Benito, Estefanía Moreno, Marta Seijo-Vila, Isabel Tundidor, Clara Andradas, María M. Caffarel, Miriam Caro-Villalobos, Leyre Urigüen, Rebeca Diez-Alarcia, Gema Moreno-Bueno, Lucía Hernández, Luis Manso, Patricia Homar-Ruano, Peter J. McCormick, Lucka Bibic, Cristina Bernadó-Morales, Joaquín Arribas, Meritxell Canals, Vicent Casadó, Enric I. Canela, Manuel Guzmán, Eduardo Pérez-Gómez, Cristina Sánchez
Proceedings of the National Academy of Sciences Feb 2019, 201815034; DOI: 10.1073/pnas.1815034116

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Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer
Sandra Blasco-Benito, Estefanía Moreno, Marta Seijo-Vila, Isabel Tundidor, Clara Andradas, María M. Caffarel, Miriam Caro-Villalobos, Leyre Urigüen, Rebeca Diez-Alarcia, Gema Moreno-Bueno, Lucía Hernández, Luis Manso, Patricia Homar-Ruano, Peter J. McCormick, Lucka Bibic, Cristina Bernadó-Morales, Joaquín Arribas, Meritxell Canals, Vicent Casadó, Enric I. Canela, Manuel Guzmán, Eduardo Pérez-Gómez, Cristina Sánchez
Proceedings of the National Academy of Sciences Feb 2019, 201815034; DOI: 10.1073/pnas.1815034116
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