Abstract 3895: Metabotropic glutamate receptor-1 as a novel target for the anti-angiogenic treatment of breast cancer.
Authors: Cecilia L. Speyer, Ali H. Hachem, Ali Assi, John A. DeVries, David H. Gorski
Journal: Cancer Research (2013)

Abstract Introduction: Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system where they mediate neuronal excitability and neurotransmitter release. However, certain cancers including melanoma and gliomas, have been shown to express various mGluR subtypes. Recently, we detected the metabotropic glutamate receptor-1 subtype (gene: GRM1; protein: mGluR1) in breast cancer and have demonstrated its role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells have been shown to express mGluR1. In light of these studies and since angiogenesis is a known prognostic indicator of early relapse in cancer correlating with a poorer prognosis, we wished to examine a potential role for mGluR1 in mediating endothelial cell proliferation and angiogenesis in breast cancer. Methods: To do this, we analyzed several primary endothelial cells for mGluR1 protein and mRNA expression and looked at their potential role in mediating cell proliferation and angiogenesis using various mGluR1 inhibitors or by silencing the gene for mGluR1 (GRM1). Cell proliferation was determined by MTT analysis or by cell counting and angiogenesis was determined in vitro using the matrigel tube formation assay. Angiogenesis was also determined in vivo using human dermal micro-endothelial cells (HDMEC) embedded in a matrigel sponge and implanted into the flanks of nude mice treated with the mGluR1 inhibitors, BAY36-7620 or Riluzole. The role of mGluR1 in mediating tumor-induced angiogenesis was also examined using the 4T1 tumor model in the presence of these same inhibitors. Results: We detected mRNA and protein expression of mGluR1 in various human endothelial cells and, using mGluR1-specific inhibitors, have demonstrated its ability to regulate cell growth as well as matrigel tube formation. Both BAY36-7620 and Riluzole inhibited cell growth and matrigel tube formation in a dose-response manner. BAY36-7620, which is a more specific-inhibitor than Riluzole, inhibited tube formation by almost 90% compared to 50% by Riluzole, at the highest doses tested. These results were confirmed using mGluR1-silenced cells. In addition, both BAY36-7620 and Riluzole inhibited angiogenesis in the in vivo matrigel sponge model by approximately 50% each, compared to vehicle treated mice. Conclusion: These results suggest a role for mGluR1 in the development and progression of breast cancer and thus, provide a potential new molecular target for the anti-angiogenic treatment of breast cancer. Citation Format: Cecilia L. Speyer, Ali H. Hachem, Ali Assi, John A. DeVries, David H. Gorski. Metabotropic glutamate receptor-1 as a novel target for the anti-angiogenic treatment of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3895. doi:10.1158/1538-7445.AM2013-3895