Abstract
Metabotropic glutamate receptors are G-protein-coupled receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.
Similar content being viewed by others
References
Coughlin SS, Ekwueme DU (2009) Breast cancer as a global health concern. Cancer Epidemiol 33(5):315–318
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96
Kurebayashi J (2009) Possible treatment strategies for triple-negative breast cancer on the basis of molecular characteristics. Breast Cancer 16(4):275–280
Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH (2007) Pathways to tamoxifen resistance. Cancer Lett 256(1):1–24
Gajria D, Chandarlapaty S (2011) HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther 11(2):263–275
Francesconi A, Duvoisin RM (1998) Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation. J Biol Chem 273(10):5615–5624
Marinissen MJ, Gutkind JS (2001) G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22(7):368–376
Pin JP, Duvoisin R (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34(1):1–26
Wang JQ, Tang Q, Parelkar NK, Liu Z, Samdani S, Choe ES, Yang L, Mao L (2004) Glutamate signaling to Ras-MAPK in striatal neurons: mechanisms for inducible gene expression and plasticity. Mol Neurobiol 29(1):1–14
Waters C, Pyne S, Pyne NJ (2004) The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin Cell Dev Biol 15(3):309–323
Bruno V, Battaglia G, Copani A, D’ Onofrio M, Di Iorio P, De Blasi A, Melchiorri D, Flor PJ, Nicoletti F (2001) Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab 21(9):1013–1033
Festoff BW (1996) Amyotrophic lateral sclerosis: current and future treatment strategies. Drugs 51(1):28–44
Mills CD, Johnson KM, Hulsebosch CE (2002) Group I metabotropic glutamate receptors in spinal cord injury: roles in neuroprotection and the development of chronic central pain. J Neurotrauma 19(1):23–42
Ronesi JA, Huber KM (2008) Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation. J Neurosci 28(2):543–547
Ronesi JA, Huber KM (2008) Metabotropic glutamate receptors and fragile × mental retardation protein: partners in translational regulation at the synapse. Sci Signal 1(5):6
Endoh T (2004) Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. Brain Res 1024(1–2):212–224
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF (2008) The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 8(3):187–198
Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8(10):1136–1144
Pollock PM, Cohen-Solal K, Sood R, Namkoong J, Martino JJ, Koganti A, Zhu H, Robbins C, Makalowska I, Shin SS, Marin Y, Roberts KG, Yudt LM, Chen A, Cheng J, Incao A, Pinkett HW, Graham CL, Dunn K, Crespo-Carbone SM, Mackason KR, Ryan KB, Sinsimer D, Goydos J, Reuhl KR, Eckhaus M, Meltzer PS, Pavan WJ, Trent JM, Chen S (2003) Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet 34(1):108–112
Shin SS, Martino JJ, Chen S (2008) Metabotropic glutamate receptors (mGlus) and cellular transformation. Neuropharmacology 55(4):396–402
Shin SS, Namkoong J, Wall BA, Gleason R, Lee HJ, Chen S (2008) Oncogenic activities of metabotropic glutamate receptor 1 (Grm1) in melanocyte transformation. Pigment Cell Melanoma Res 21(3):368–378
Miller RG, Mitchell JD, Lyon M, Moore DH (2003) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord 4(3):191–206
Namkoong J, Shin SS, Lee HJ, Marin YE, Wall BA, Goydos JS, Chen S (2007) Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma. Cancer Res 67(5):2298–2305
Marin YE, Namkoong J, Cohen-Solal K, Shin SS, Martino JJ, Oka M, Chen S (2006) Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCepsilon. Cell Signal 18(8):1279–1286
Shin SS, Wall BA, Goydos JS, Chen S (2010) AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1). Pigment Cell Melanoma Res 23(1):103–111
Ohtani Y, Harada T, Funasaka Y, Nakao K, Takahara C, Abdel-Daim M, Sakai N, Saito N, Nishigori C, Aiba A (2008) Metabotropic glutamate receptor subtype-1 is essential for in vivo growth of melanoma. Oncogene 27(57):7162–7170
Yip D, Le MN, Chan JL, Lee JH, Mehnert JA, Yudd A, Kempf J, Shih WJ, Chen S, Goydos JS (2009) A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma. Clin Cancer Res 15(11):3896–3902
Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24(28):6352–6361
Scartabelli T, Gerace E, Landucci E, Moroni F, Pellegrini-Giampietro DE (2008) Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway: a novel postconditioning strategy? Neuropharmacology 55(4):509–516
Zhang RD, Fidler IJ, Price JE (1991) Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. Invasion Metastasis 11(4):204–215
Carroll FY, Stolle A, Beart PM, Voerste A, Brabet I, Mauler F, Joly C, Antonicek H, Bockaert J, Muller T, Pin JP, Prezeau L (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol 59(5):965–973
Noh KM, Hwang JY, Shin HC, Koh JY (2000) A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol Dis 7(4):375–383
Khan AJ, Wall B, Ahlawat S, Green C, Schiff D, Mehnert JM, Goydos JS, Chen S, Haffty BG (2011) Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res 17(7):1807–1814
Kuperwasser C, Dessain S, Bierbaum BE, Garnet D, Sperandio K, Gauvin GP, Naber SP, Weinberg RA, Rosenblatt M (2005) A mouse model of human breast cancer metastasis to human bone. Cancer Res 65(14):6130–6138
Acknowledgments
We are grateful to Dr. Stephen Ethier for kindly providing us with his SUM cell lines [34]. This study is supported by an Advanced Clinical Research Award in Breast Cancer funded by the Conquer Cancer Foundation of the American Society of Clinical Oncology and the Breast Cancer Research Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Speyer, C.L., Smith, J.S., Banda, M. et al. Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer. Breast Cancer Res Treat 132, 565–573 (2012). https://doi.org/10.1007/s10549-011-1624-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-011-1624-x