RT Journal Article
T1 Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer
A1 Pérez Gómez, Eduardo
A1 Andradas, Clara
A1 Blasco Benito, Sandra
A1 Caffarel, María M.
A1 García Taboada, Elena
A1 Villa Morales, María
A1 Moreno, Estefania
A1 Hamann, Sigrid
A1 Martin Villar, Ester
A1 Flores, Juana M.
A1 Wenners, Antonia
A1 Alkatout, Ibrahim
A1 Klapper, Wolfram
A1 Roecken, Christoph
A1 Bronsert, Peter
A1 Stickeler, Elmar
A1 Staebler, Annette
A1 Bauer, Maret
A1 Arnold, Norbert
A1 Soriano, Joaquim
A1 Pérez Martínez, Manuel
A1 Megias, Diego
A1 Moreno Bueno, Gema
A1 Ortega Gutiérrez, Silvia
A1 Artola, Marta
A1 Vázquez Villa, María Del Henar
A1 Quintanilla, Miguel
A1 Fernandez-Piqueras, Jose
A1 Canela, Enric I.
A1 McCormick, Peter J.
A1 Guzmán Pastor, Manuel
A1 Sánchez García, María Cristina
AB Background: Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown.Methods: We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tubingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (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 colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided.Results: We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P =.009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P =.003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P =.009). 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 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells.Conclusions: Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors.
PB Oxford University Press
SN 0027-8874
YR 2015
FD 2015-06-01
LK https://hdl.handle.net/20.500.14352/114393
UL https://hdl.handle.net/20.500.14352/114393
LA eng
NO Pérez-Gómez, E., Andradas, C., Blasco-Benito, S., Caffarel, M. M., García-Taboada, E., Villa-Morales, M., Moreno, E., Hamann, S., Martín-Villar, E., Flores, J. M., Wenners, A., Alkatout, I., Klapper, W., Röcken, C., Bronsert, P., Stickeler, E.,  Staebler, A., Bauer, M., Arnold, N., Soriano, J., Pérez-Martínez, M., Megías, D., Moreno-Bueno, G., Ortega-Gutiérrez, S., Artola, M., Vázquez-Villa, H., Quintanilla, M., Fernández-Piqueras, J., Canela, E. I., McCormick, P. J., Guzmán, J., Sánchez, C. Role of Cannabinoid Receptor CB2 in HER2 Pro-oncogenic Signaling in Breast Cancer, JNCI: J. Nat. Cancer Inst. 2015, 107 (6), djv077
NO Ministería de Economía y Competetividad
NO Comunidad de Madrid
NO Fundación Mutua Madrileña
NO Sandra Ibarra Foundation
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 6 abr 2025