Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma

Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and NF1. Our lab was the first to identify yet another driver of melanoma, Metabotropic Glutamate Receptor 1 (protein: mGluR1, mouse gene: Grm1, human gene: GRM1), upstream of the MAPK and PI3K/AKT pathways. Binding of glutamate, the natural ligand of mGluR1, activates MAPK and PI3K/AKT pathways and sets in motion the deregulated cellular responses in cell growth, cell survival, and cell metastasis. In this review, we will assess the proposed modes of action that mediate the oncogenic properties of mGluR1 in melanoma and possible application of anti-glutamatergic signaling modulator(s) as therapeutic strategy for the treatment of melanomas.

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Glutamate Secretion and Metabotropic Glutamate Receptor 1 Expression during Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Cell Proliferation

PLoS Pathogens ◽

10.1371/journal.ppat.1004389 ◽

2014 ◽

Vol 10 (10) ◽

pp. e1004389 ◽

Cited By ~ 14

Author(s):

Mohanan Valiya Veettil ◽

Dipanjan Dutta ◽

Virginie Bottero ◽

Chirosree Bandyopadhyay ◽

Olsi Gjyshi ◽

...

Keyword(s):

Cell Proliferation ◽

Glutamate Receptor ◽

Kaposi's Sarcoma ◽

Metabotropic Glutamate Receptor ◽

Kaposi’S Sarcoma ◽

Herpesvirus Infection ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 1 ◽

Kaposi's Sarcoma Associated Herpesvirus ◽

Kaposi’S Sarcoma Associated Herpesvirus

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Metabotropic glutamate receptor 1 is associated with unfavorable prognosis in ER-negative and triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-020-79248-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Anna E. M. Bastiaansen ◽

A. Mieke Timmermans ◽

Marcel Smid ◽

Carolien H. M. van Deurzen ◽

Esther S. P. Hulsenboom ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Glutamate Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Metabotropic Glutamate Receptor ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 1 ◽

Novel Target ◽

Cancer Tissues

AbstractNew therapies are an urgent medical need in all breast cancer subgroups. Metabotropic glutamate receptor 1 (mGluR1) is suggested as a potential new molecular target. We examined the prevalence mGluR1 expression in different clinically relevant breast cancer subgroups and determined its association with prognosis. In this retrospective cohort, 394 consecutive primary breast cancer tissues were incorporated into a tissue microarray and immunohistochemically stained for mGluR1. The prevalence of mGluR1 protein expression in different breast cancer subgroups was evaluated and correlated with metastasis-free survival (MFS) and overall survival (OS). In total, 56% (n = 219) breast cancer tissues had mGluR1 expression. In estrogen receptor (ER)-negative tumors, 31% (n = 18/58) had mGluR1 expression that was significantly associated with MFS (HR 5.00, 95% CI 1.03–24.35, p = 0.046) in multivariate analysis, independently from other prognostic factors. Of the 44 triple-negative breast cancer (TNBC), 25% (n = 11) expressed mGluR1. mGluR1 expression in TNBC was significantly associated with shorter MFS (HR 8.60, 95% CI 1.06–20.39, p = 0.044) and with poor OS (HR 16.07, 95% CI 1.16–223.10, p = 0.039). In conclusion, mGluR1 is frequently expressed in breast cancer. In ER-negative breast cancer and in TNBC mGluR1 protein expression is an unfavorable prognostic marker. This study provides rationale to explore mGluR1 as a novel target for breast cancer treatment, especially for the more aggressive TNBC.

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