Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.

Clara Andradas,Cristina Sánchez,Rodrigo Hernando-Llorente,Antonia Wenners,Norbert Arnold,Leyre Urigüen,Eduardo Pérez-Gómez,Wolfram Klapper,Miguel Quintanilla,Sigrid Hamann,Sandra Blasco-Benito,Sonia Castillo-Lluva,J Silvio Gutkind,Elena García-Taboada,Manuel Guzmán,Alba Juanes-García,Miguel Vicente‐Manzanares ,İbrahim Alkatout ,Patrícia Dillenburg-Pilla ,Christoph Röcken ,Diego Megı́as ,Joaquím Soriano ,M Bauer ,Rebeca Dı́ez-Alarcia

doi:10.18632/oncotarget.10206

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.

Highlights

G protein-coupled receptors (GPCRs), the largest superfamily of receptors, are involved in a wide variety of biological functions [1], and their dysfunction contributes to many human diseases [2]
GPR55 mRNA levels were elevated in basal tumors with respect to the other molecular subtypes of breast cancer in two datasets containing a total of 2557 human samples [20, 22] (Figures 1E and 1F), and in basal human breast cancer cell lines with respect to cell lines with other molecular features (Figure 1G)
These findings show that an elevated GPR55 expression is associated with the highly aggressive basal/triple-negative breast cancer subtype, higher probability to develop metastases, and poor patient prognosis

Summary

Introduction

G protein-coupled receptors (GPCRs), the largest superfamily of receptors, are involved in a wide variety of biological functions [1], and their dysfunction contributes to many human diseases [2]. Increasing evidence indicates that aberrant GPCR signaling is implicated in cancer initiation and progression [3,4,5], and the search for new GPCRs involved in these processes has become a strategy for the development of new cancer treatments. Increasing evidence supports that GPR55 is an important component of the molecular circuitry that controls cancer cell behavior. This receptor has been shown to drive cancer cell proliferation in in vitro and/or in vivo models of glioblastoma [10]; prostate [11], ovarian [11] and skin carcinoma [12]; melanoma [13], and non-small lung cancer [14]. Here we aimed at shedding light on these two particular issues by focusing on breast cancer, one of the leading causes of death in women [18]

Methods

Results

Conclusion