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)
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.
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.
↵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.
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.
