Cannabinoid receptor CB2 drives HER2 pro-oncogenic signaling in breast cancer

Eduardo Pérez-Gómez (Lead Author), Clara Andradas, Sandra Blasco-Benito, María M. Caffarel, Elena García-Taboada , María Villa-Morales , Estefanía Moreno , Sigrid Hamann , Ester Martín-Villar , Juana M. Flores , Antonia Wenners , Ibrahim Alkatout , Wolfram Klapper , Christoph Röcken , Peter Bronsert , Elmar Stickeler , Annette Staebler, Maret Bauer , Norbert Arnold , Joaquim Soriano Manuel Pérez-Martínez , Diego Megías , Gema Moreno-Bueno, Silvia Ortega-Gutiérrez, Marta Artola, Henar Vázquez-Villa, Miguel Quintanilla , José Fernández-Piqueras, Enric I. Canela, Peter J. McCormick, Manuel Guzmán, Cristina Sánchez

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Abstract

Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different models of cancer. However, the biological role of these receptors in tumor physio-pathology is still unknown. We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen and Freiburg between 1997 and 2010. CB2 mRNA expression was also analyzed in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the HER2 rat ortholog (neu) and lacks CB2, and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by co-localization, coimmunoprecipitation and proximity ligation assays. We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis. We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade, and that an increased CB2 expression activates the HER2 prooncogenic signaling machinery at the level of the tyrosine kinase c-SRC. Finally, HER2 and CB2 form heteromers in cancer cells. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and suggest that CB2 may be a biomarker with prognostic value in these tumors.
Original languageEnglish
Article numberdjv077
JournalJournal of the National Cancer Institute
Volume107
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

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