We demonstrate here that functional
NMDAR1 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 to >800 microM and from 200 to 300 microM 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 5 days. All of these data point to active NMDAR receptors being expressed by most breast
cancers, and having an important influence on their survival.