Abstract 1578: The role of metabotropic glutamate receptor-1 in breast cancer tumor progression

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity and feedback inhibition of neurotransmitter release. However, recent studies suggest that these receptors are also present and functional in various cancer types, including melanoma and prostate cancer cells. In addition, brain endothelial cells were recently shown to express mGluR1 receptors and to mediate VEGF-induced endothelial cell proliferation both in vivo and in vitro. These results suggest a role for mGluR1 in mediating angiogenesis, a process that is required for cancer tumors to grow and metastasize. Both VEGF levels and angiogenesis are independent prognostic indicators in primary breast cancer patients with their presence being associated with early relapse. Therefore, we wished to examine a potential role for mGluR1 in mediating VEGF-induced breast cancer tumor progression. Methods: To do this, we analyzed several breast cancer cell lines as well as primary endothelial cells for mGluR1 protein and mRNA expression and looked at their potential role in mediating cell growth, angiogenesis and tumor formation in a mouse xenograph model. The role of mGluR1 on cell growth was determined using an MTT assay and by counting isolated nuclei with a Coulter counter in the presence and absence of BAY36-7620 and Riluzole, specific non-competitive inhibitors of mGluR1. The angiogenic potential of endothelial cells and the role of mGluR1 in mediating this process were measured using a matrigel tube formation assay in the presence and absence of BAY36-7620 and Riluzole. Lastly, the effect of mGluR1 on tumor formation and angiogenesis in vivo was determined by measuring tumor growth and blood vessel formation in a xenograft model derived from cell lines expressing high levels of mGluR1 and treated with either the mGluR1 inhibitors or vehicle. Results: The results of this study show strong mRNA and protein expression of mGluR1 in several breast cancer cell lines as well as in HUVECs and human dermal micro-endothelial cells (HDMEC). Cell growth, in the presence of either BAY36-7620 or Riluzole, inhibited cell growth in all these cells in a dose-response manner and completely inhibited VEGF-induced matrigel tube formation of HUVECs and HDMEC. In addition, tumor growth in a xenograft model using MBA231 cells, which expressed high levels of mGluR1, was inhibited by 30% and 50% in the presence of 9 mg/kg and 18 mg/kg Riluzole, respectively. Conclusion: By inhibiting both breast cancer cell growth and angiogenesis, these results implicate mGluR1 as a major player in the development and progression of breast cancer and thus suggests that mGluR1 may serve as a useful therapeutic target in the treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1578.