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

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.

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment

“…Andradas et al found an association between GPR55 expression and basal/TNBC subtype. They analyzed the publicly available The Cancer Genome Atlas (TCGA) microarray data sets and found that women with basal/TNBC and high tumor GPR55 mRNA expression had reduced overall survival and reduced metastasis-free survival in comparisson to those with low GPR55 mRNA levels [50]. There is no clinical evidence evaluating the effect of exogenous or endogenous cananbinoids on treatment outcomes and/or disease prognosis of any BC subtype.…”

Insights into the effects of the endocannabinoid system in cancer: a review

“…Levels of the orphan GPR55 were associated with high proliferation rates of tumour cells. In this context, in vitro and in vivo studies undertaken in several tumour models, including pancreas, breast, brain (Andradas et al, ; Andradas et al, ), prostate, ovary (Pineiro et al, ) and skin carcinomas (Perez‐Gomez et al, ) reported that GPR55 receptors were implicated in the proliferation and progression of cancer. This may be attributed to GPR55 activation by the agonist L‐α‐lysophosphatidylinositol (LPI) (Ford et al, ; Hofmann et al, ) and, in patients with ovarian cancer, elevated levels of LPI were detected in plasma (Xiao et al, ; Sutphen et al, ).…”

GPR55: a new promising target for metabolism?

“…The effects of cannabinoids through GPR55 have been investigated using different pharmacological approaches such as the [ 35 S]GTPγS-binding assay (measurement of GPR55 agonist-induced GDP-GTP exchange as an indicator of receptor activation), intracellular Ca 2+ transients, phosphorylation of ERK or activation of GTPase proteins and β-arrestin recruitment models (Oka et al 2007, 2009, Ryberg et al 2007, Lauckner et al 2008, WaldeckWeiermair et al 2008, Henstridge et al 2009, Kapur et al 2009, Ross 2009, 2011, Pertwee et al 2010, Whyte et al 2015, Zeng et al 2015. Moreover, in vivo studies have allowed a better knowledge of the physiological relevance of GPR55 signaling in processes such as energy metabolism (Romero-Zerbo et al 2011, Moreno-Navarrete et al 2012, Imbernon et al 2014, inflammation (Staton et al 2008), vascular function (Daly et al 2010), bone physiology (Whyte et al 2009), cancer (Perez-Gomez et al 2012, Andradas et al 2016 and GI disorders (Hasenoehrl et al 2016). Taking into account the large amount of physiological systems in which GPR55 is involved, the design of potent and tissue-specific GPR55 ligands remains an important field to develop new drugs.…”