Metabotropic Glutamate Receptor 1 Expression and Its Polymorphic Variants Associate with Breast Cancer Phenotypes

Abstract

Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation and differentiation, has been implicated in melanomagenesis, with ectopic expression of GRM1 causing malignant transformation of melanocytes. This study was undertaken to evaluate GRM1 expression and polymorphic variants in GRM1 for associations with breast cancer phenotypes. Three single nucleotide polymorphisms (SNPs) in GRM1 were evaluated for associations with breast cancer clinicopathologic variables. GRM1 expression was evaluated in human normal and cancerous breast tissue and for in vitro response to hormonal manipulation. Genotyping was performed on genomic DNA from over 1,000 breast cancer patients. Rs6923492 and rs362962 genotypes associated with age at diagnosis that was highly dependent upon the breast cancer molecular phenotype. The rs362962 TT genotype also associated with risk of estrogen receptor or progesterone receptor positive breast cancer. In vitro analysis showed increased GRM1 expression in breast cancer cells treated with estrogen or the combination of estrogen and progesterone, but reduced GRM1 expression with tamoxifen treatment. Evaluation of GRM1 expression in human breast tumor specimens demonstrated significant correlations between GRM1 staining with tissue type and molecular features. Furthermore, analysis of gene expression data from primary breast tumors showed that high GRM1 expression correlated with a shorter distant metastasis-free survival as compared to low GRM1 expression in tamoxifen-treated patients. Additionally, induced knockdown of GRM1 in an estrogen receptor positive breast cancer cell line correlated with reduced cell proliferation. Taken together, these findings suggest a functional role for GRM1 in breast cancer.

Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine

“…We reasoned that glutamate might act through a glutamate receptor, such as metabotropic glutamate receptor 1 (GRM1), which is expressed by some breast cancers (Mehta et al, 2013; Speyer et al, 2012). However, HIF1α induction by glutamate in TNBC lines was not blocked by glutamate receptor antagonists such as the GRM1 antagonists, BAY 36-7620 and JNJ 16259685; or the GRM2/3 antagonist, LY 341495 (data not shown).…”

“…Glutamate can also alter cancer cell behavior by modulating ionotropic glutamate receptors, such as the AMPA receptor and NMDA receptors, and metabotropic glutamate receptors (Stepulak et al, 2014; Willard and Koochekpour, 2013). Indeed, a role for the NMDA receptor and metabotropic glutamate receptor-1 in breast cancer has been previously suggested (Mehta et al, 2013; North et al, 2010; Speyer et al, 2012). Secretion of glutamate by glioblastoma cells promotes invasion and tumorigenesis at least partly by causing neuroexcitatory death of surrounding normal brain cells and by activating AMPA receptors (Stepulak et al, 2014; Willard and Koochekpour, 2013).…”

Identification of Novel GRM1 Mutations and Single Nucleotide Polymorphisms in Prostate Cancer Cell Lines and Tissues

“…Previous study using 1000 breast cancer patients showed association of this SNP in ER+/PR+ ductal carcinoma in TT-genotype carrier with later age at diagnosis (4.9 years) as compared to either TC- and CC-genotype carriers [32]. However, no association was found with melanoma susceptibility [33].…”

Metabotropic glutamate receptors in cancer

“…In particular, mGluRs have been shown empirically to be the predominant mediators of glutamatergic signaling in many cancers (Khan et al, 2011; Koochekpour, 2013; Martino et al, 2013; Speyer et al, 2014; Teh and Chen, 2012; Zhang et al, 2015). The mechanisms by which mGluRs modulate peripheral cell transformation and tumor growth are postulated to be either ectopic expression of wild type mGluRs, increased proliferative signals arising from receptor overexpression, mutations, or expression of polymorphic variants (Ali et al, 2014; Brocke et al, 2010; Mehta et al, 2013; Namkoong et al, 2007; Wall et al, 2014; Zhang et al, 2015). …”

“…While the contributions of mGluR1 overexpression in breast cancer were explored, a correlation between the polymorphic variants of GRM1 and breast cancer subtypes was demonstrated (Mehta et al, 2013). Earlier, in a genetic association study examining correlation of 3 single nucleotide polymorphisms in GRM1 and melanoma susceptibility showed higher frequency of one of the polymorphisms in GRM1-positive melanoma patients compared to controls.…”