Abstract 1206: Metabotropic glutamate receptor 1 functions as an oncogene in the progression of triple negative breast cancer
Authors: Banda Malathi , Speyer Cecilia L. , Tait Larry , Miller Fred R. , Gorski David H. 
Published: August 2012

Abstract
Introduction: L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors. mGluR1 (gene: GRM1) is included in Group I of these receptors and have been shown to activate phosphatidylinositol-calcium second messenger system. Aberrant extracellular glutamate signaling has been implicated in carcinogenesis; specifically, the aberrant expression of mGluR1 in melanocytes plays a critical role in the development of melanoma. Previously in our laboratory, we detected mGRM1 expression in triple negative breast cancer cells. We therefore evaluated its role in regulating the phenotype of these cells and found that mGluR1 expression is oncogenic in triple negative breast cancer (TNBC) progression. Methods: We determined the role of mGluR1 in TNBC progression using the MCF-10 triple negative series of cell lines, which represent the progression from normal mammary epithelium (MCF10A) to atypical hyperplasia (MCF10AT1) to ductal carcinoma in situ (MCF10.DCIS.com), and finally to malignant (MCF10.CA1D). GRM1 was overexpressed in MCF10A and MCF10AT1 and silenced MCF10.DCIS.com and MCF10.CA1D. We then determined whether mGRM1 has a transforming role through in vitro studies of proliferation, invasion, migration and anchorage-independent growth. We also inhibited mGluR1 signaling using two pharmacologic inhibitors: Riluzole, which is FDA-approved for amyotropic lateral sclerosis, and BAY36-7620, which is a specific noncompetitive inhibitor of mGluR1. Effects were evaluated on proliferation and anchorage independent growth. Finally, MCF10AT1 cells were transduced with a lentiviral construct driving mGluR1 expression and injected into athymic nude mice. The growth and histology of the resultant xenografts were compared with control LacZ transduced cells. Results: mGluR1 overexpression increased proliferation, anchorage-independent growth, and invasiveness in MCF10AT1 and not in MCF10A cells, while knockdown of mGluR1 expression resulted in a decrease in proliferation, anchorage independent growth and invasiveness in MCF10.CA1D cells. Pharmacologic inhibition of mGluR1 signaling in MCF10.CA1D cells resulted in a decrease in proliferation and anchorage independent growth. Transduction of MCF10AT1 cells with GRM1 resulted in transformation to carcinoma in 10/11 of the resultant xenografts compared to 2/9 for wild type and 3/11 for LacZ controls. Conclusions: mGluR1 expression and activity increases cell proliferation, anchorage independent growth, and invasion in vitro. In vivo, mGluR1 drives progression of MCF10AT1 cells from hyperplastic lesions to frank carcinoma. We therefore conclude that mGRM1 plays a role of an oncogene in the progression of TNBC and represents a therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1206. doi:1538-7445.AM2012-1206