The role of NMDA receptors subunits in the progression of inflammatory breast cancer (IBC)

Abstract

Inflammatory Breast Cancer (IBC) has a 73% incidence of metastasis to the brain as compared to other cancer types like breast, lung, and bone cancer. Previous research showed that tumor cells from different breast cancer subtypes (‐HR / ‐HER2) and (‐HR / + HER2) have a high incidence of crossing the blood‐brain barrier and inducing increased expression of glutamate receptors NMDA subunits (NMDAR1 and NMDR2) in the brain. IBC is the most aggressive and rare type of breast cancer. The absence of a solid tumor is replaced by swelling, redness, and skin changes, resulting in many cases in misdiagnosis of an infection in the invasion and migration phase; this type of cancer blocks blood and lymphatic vessels in the breast's skin, causing local inflammation and rapid metastasis. However, little is known of the role that these glutamatergic receptors have in the development and/or progression of IBC. The present work provides a new understanding of the cellular and molecular effects NMDA receptors (NMDAR) have on oncogenic phenotypes in IBC. The detection and quantification of the NMDAR were evaluated by RT‐qPCR, Western blot, and immunofluorescence (IF) techniques in deferments breast cancer cell lines (MCF7, MDA‐MB‐231) and IBC cell lines (SUM149, and SUM190). Also, NMDAR antagonists (memantine and dizocilpine “MK‐801”) were used in 2D and 3D cell cultures to see the pro‐oncogenic effects of migration and proliferation in cell models. In addition to this, the autocrine regulation of Glutamate in IBC cell lines is verified. Results showed a significant increase in the expression of NMDARs in IBC cell lines. In the functional cell culture assays with NMDAR antagonists, a decrease in migration and proliferation in IBC cell lines was found. These findings may be related to the high aggressiveness and the high rate of metastasis by IBC within the brain. Our results have high clinical relevance since having extensive knowledge of the role of NMDARs in IBC progression could complement therapeutic approaches for patients with IBC.