title: Metabotropic glutamate receptor-1 as a novel target for the antiangiogenic treatment of breast cancer.
abstract: Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
authors.affiliation: Tumor Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Speyer
authors.affiliation: University of Michigan, Dearborn, Michigan, United States of America.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Hachem
authors.affiliation: University of Michigan, Dearborn, Michigan, United States of America.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Assi
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: DeVries
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America; Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Gorski
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C505455:6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide; C425484:BAY36-7620; D001562:Benzimidazoles; D009281:Naphthalenes; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1