Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer

Abstract

Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.

Revealing the Potential Application of EC-Synthetic Retinoid Analogues in Anticancer Therapy

“…Glutamate is an essential molecule for cells, especially cancer cells due to its paracrine effect on intracellular and extracellular communications where even the small changes in its levels significantly impact the cellular transformation and cancer progression [99][100][101]. The extracellular glutamate is mainly required for intercellular communication and activation of survival pathways, like the MAPK and PI3K pathways, promoting growth and invasion [101,102].…”

Critical Neurotransmitters in the Neuroimmune Network

“…The use of inhibitors against mGluR 1 and PSMA in preclinical models regressed prostate cancer (282). Similarly, mGluR 1 signaling in triple negative breast cancers promotes their progression, angiogenesis, and metastasis (260,283). Also, mGluR 1 and NMDAR antagonists increased dendritic branching and decreased the motility, migration and proliferation of human melanoma cells in xenograft models by inhibiting dynamin GTPase and blocking ERK1/2 pathway (284)(285)(286).…”

“…Also, mGluR 1 and NMDAR antagonists increased dendritic branching and decreased the motility, migration and proliferation of human melanoma cells in xenograft models by inhibiting dynamin GTPase and blocking ERK1/2 pathway ( 284 – 286 ). Apparently, mGluR 1 signaling has a direct effect on tumor cell growth and survival but it also increases inflammation within the tumor microenvironment by upregulating the production of inflammatory chemoattractants such as CXCL1, IL-6, and IL-8 and inducing neutrophil transmigration ( 260 ). Thus, blocking specific GluR signaling, which is exploited by tumors to survive and grow, and enhance tumor-promoting inflammation, could be a potential therapeutic approach to treat tumors and some autoimmune inflammatory diseases.…”

Metabotropic glutamate receptor 1 is associated with unfavorable prognosis in ER-negative and triple-negative breast cancer

“…Second, reduction of mGluR1 activity in TNBC results in tumor suppression and reduced angiogenesis 18 . Finally, mGluR1 can operate as a regulator of inflammation by creating an immunosuppressive tumor microenvironment resulting in inhibition of antitumor activity 28 , 29 . With regard to the clinical connection between expression of mGluR1 and aggressiveness, in the entire cohort there was no association between the expression of mGluR1 and MFS or OS.…”