Research Papers:
Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer
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Abstract
Clara Andradas1,2, Sandra Blasco-Benito1,2, Sonia Castillo-Lluva1, Patricia Dillenburg-Pilla3, Rebeca Diez-Alarcia4, Alba Juanes-García5, Elena García-Taboada1, Rodrigo Hernando-Llorente1, Joaquim Soriano6, Sigrid Hamann7, Antonia Wenners7, Ibrahim Alkatout7, Wolfram Klapper8, Christoph Rocken8, Maret Bauer7, Norbert Arnold7, Miguel Quintanilla9, Diego Megías6, Miguel Vicente-Manzanares5, Leyre Urigüen4, J. Silvio Gutkind3,10, Manuel Guzmán1,11, Eduardo Pérez-Gómez1,2, Cristina Sánchez1,2
1Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain
2Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
3Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
4Department of Pharmacology, University of The Basque Country UPV/EHU, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
5Instituto de Investigación Sanitaria Hospital Universitario de la Princesa and Universidad Autónoma de Madrid, School of Medicine, Madrid, Spain
6Spanish National Cancer Research Centre (CNIO), Madrid, Spain
7Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
8Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
9Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
10Department of Pharmacology, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
11Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
Correspondence to:
Cristina Sánchez, email: [email protected]
Eduardo Pérez-Gómez, email: [email protected]
Keywords: GPR55, G protein-coupled receptor, cannabinoids, metastasis, triple-negative breast cancer
Received: February 16, 2016 Accepted: June 04, 2016 Published: June 21, 2016
ABSTRACT
The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.
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PII: 10206