title: Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer.
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.
authors.affiliation: Breast Cancer Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Speyer
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Smith
authors.forename: Malathi
authors.initials: M
authors.lastname: Banda
authors.forename: John A
authors.initials: JA
authors.lastname: DeVries
authors.forename: Tassia
authors.initials: T
authors.lastname: Mekani
authors.forename: David H
authors.initials: DH
authors.lastname: Gorski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D016318:Quisqualic Acid / Q000494:pharmacology; D034622:RNA Interference; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019782:Riluzole / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C425484:BAY36-7620; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009281:Naphthalenes; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D019782:Riluzole; D016318:Quisqualic Acid