Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer

• Published in: Breast cancer research and treatment Vol. 132; no. 2; pp. 565 - 573
• Main Authors: Speyer, Cecilia L., Smith, Jennifer S., Banda, Malathi, DeVries, John A., Mekani, Tassia, Gorski, David H.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-04-2012; Springer; Springer Nature B.V
• Subjects: Amino acids; Amyotrophic lateral sclerosis; Animals; Annexin V; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer research; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Central nervous system; Data processing; Dose-Response Relationship, Drug; Drug development; Drug therapy; Excitability; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - administration & dosage; Excitatory Amino Acid Antagonists - pharmacology; Feedback inhibition; Female; G protein-coupled receptors; Genes; Glutamate; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Gynecology. Andrology. Obstetrics; Health aspects; Humans; Injections, Intraperitoneal; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Melanoma; Mice; Mice, Nude; Naphthalenes - administration & dosage; Naphthalenes - pharmacology; Neurotransmitter release; Oncology; Phenotype; Plasticity (synaptic); Poly(ADP-ribose) polymerase; Preclinical Study; Proteins; Quisqualic Acid - pharmacology; Receptors, Metabotropic Glutamate - drug effects; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Riluzole; Riluzole - administration & dosage; Riluzole - pharmacology; RNA Interference; Signal Transduction - drug effects; Time Factors; Toxicity; Transfection; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; Xenografts; mGluR1; Breast cancer; GRM1; Apoptosis; Breast disease; Targeting; Targeted therapy; mglu1 glutamate receptor; Malignant tumor; Mammary gland diseases; Treatment; Cell death; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1624-x

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.