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Sci Rep. 2018 Oct 30;8(1):16008. doi: 10.1038/s41598-018-34502-8.

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

Author information

1
Cancer Biology Graduate Program, Wayne State University, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.
2
Central Michigan University College of Medicine, 1000 Houghton Ave., Saginaw, MI, 48602, USA.
3
University of Michigan School of Medicine, M4101 Medical Science Building I - C Wing, 1301 Catherine St., Ann Arbor, MI, 48109-5624, USA.
4
Oakland University William Beaumont School of Medicine, 2200 N. Squirrel Road, Rochester, MI, 48309, USA.
5
Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.
6
Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA.
7
Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA. clspeyer@wayne.edu.
8
Tumor Microenvironment Program, Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI, 48201, USA. clspeyer@wayne.edu.

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.

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