Breast cancer expresses functional NMDA receptors

Abstract

We demonstrate here that functional NMDAR1 receptors and NMDAR2 receptors are expressed by Mcf-7 and SKBR3 breast cancer cell lines, and possibly by most or all high-grade breast tumors, and that these receptors are important for the growth of human breast cancer xenografts in mice. RT-PCR demonstrated mRNA for both NMDAR1 and NMDAR2 receptors are expressed in both Mcf-7 and SKBR3 cell lines, and these messages likely have sequences identical to those reported for human mRNAs. Proteins of the expected respective sizes 120 and 170 KD are generated from these mRNAs by the tumor cells. Cell growth was found to be significantly (p<0.0001) impaired down to 10% of normal growth by the irreversible NMDAR1 antagonists MK-801 and memantine with IC 50s ranging from 600–>800 μM and from 200–300 μM for the two lines. Paradoxically, memantine with a lower binding affinity had the greater influence of the two inhibitors on cell viability. Immunohistochemical examination of high-grade invasive ductal and lobular breast cancer with our polyclonal antibodies against a peptide (-Met-Ser-Ile-Tyr-Ser-Asp-Lys-Ser-Ile-His-) in the extracellular domain of the NMDAR1 receptor gave specific positive staining for the receptor in all 10 cases examined. Positive staining was chiefly concentrated at the membranes of these tumor tissues. No staining with these antibodies was found for normal breast and kidney tissues. When Mcf-7 cells were grown as tumor xenografts in nu/nu mice, the growth of these tumors was completely arrested by daily treatments with MK-801 over five days. All of these data point to active NMDAR receptors being expressed by most breast cancers, and having an important influence on their survival.

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

“…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).…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…Clinically, serum glutamate positively correlates with cancer progression and invasiveness [128], and the protumor effects of glutamate appear to be largely mediated by NMDARs. NMDARs have been identified in a wide variety of tumor types and cancer cell lines (Table 2), and, regardless of subunit configuration, NMDAR blockade reduces both cancer cell proliferation and invasiveness across many different cancers [129][130][131][132][133][134][135][136][137]. While the precise mechanisms underpinning the NMDAR-mediated effects on proliferation are poorly understood, there are clues.…”

Experimental Therapeutics in Breast Cancer Cells

“…Interestingly, recent report revealed that SKBR3 expressed NMDAR1 and NMDAR2 receptors, both of which are important calcium channels. These receptors are reported to be essential for the growth of human breast cancer xenografts in mice (North et al, 2010). This SKBR3 cell line with high expression of HER2 protein has long been used in various research.…”