Pharmacological inhibition of NMDA receptors reduces migration and viability in triple-negative inflammatory breast cancer cell lines

NMDA receptors (NMDARs), best known for their role in neuronal signaling, have been linked to breast cancer progression and metastasis, but their involvement in Inflammatory Breast Cancer (IBC) remains unexplored. IBC is a rare, invasive subtype with rapid progression, poor prognosis, and a high propensity for brain metastasis. Given the neuronal functions of NMDARs and IBC’s high brain metastasis rates, we hypothesized that MNDARs may contribute to IBC’s aggressive phenotype and represent a novel therapeutic target.

IBC cell lines (SUM149PT and SUM190PT) and non-IBC controls (MBA-MB-231 and MCF7) were cultured in 2D and 3D systems to assess NMDAR mRNA and protein expression. Immunochemistry followed by confocal microscopy was performed to localize NMDARs within all cell lines. Functional studies tested the effects of NMDAR antagonist MK-801 (Dizocilpine) and Memantine on IBC’s migration and 3D colony formation.

NMDAR1 mRNA was significantly overexpressed in SUM149PT cells compared to MCF7, while NMDAR2B mRNA was significantly higher in both IBC lines. Protein analysis showed increased NMDAR1 in both IBC lines and NMDAR2B elevated only in SUM149PT. Immunochemistry and confocal microscopy confirmed both subunits in all lines, predominantly localized in cytoplasmic and perinuclear regions. Functionally, MK-801 reduced viability (IC₅₀ = 200–400 µM), decreased SUM149PT migration by ~ 50%, and suppressed colony formation by ~ 90% in both IBC cell lines, indicating a role for NMDAR signaling in IBC growth and motility.

This study provides the first evidence linking NMDARs to IBC progression. Elevated expression and inhibition-sensitive aggressive phenotypes suggest NMDARs as potential biomarkers and therapeutic targets in IBC.