Myocyte Enhancer Factor 2C as a New Player in Human Breast Cancer Brain Metastases

Abstract

Myocyte enhancer factor 2C (MEF2C) is increasingly expressed in mice along with breast cancer brain metastases (BCBM) development. We aim to ascertain MEF2C expression in human BCBM, establish the relationship with disease severity, disclose the involvement of vascular endothelial growth factor receptor-2 (VEGFR-2) and β-catenin, also known as KDR and CTNNB1, respectively, and investigate if matched primary tumors express the protein. We studied resected BCBM for the expression of MEF2C, VEGFR-2, and ß-catenin, as well as proliferation (Ki-67) and epithelial (pan Cytokeratin) markers, and related experimental and clinical data. MEF2C expression was further assessed in matched primary tumors and non-BCBM samples used as controls. MEF2C expression was observed in BCBM, but not in controls, and was categorized into three phenotypes (P): P1, with extranuclear location; P2, with extranuclear and nuclear staining, and P3, with nuclear location. Nuclear translocation increased with metastases extension and Ki-67-positive cells number. P1 was associated with higher VEFGR-2 plasma membrane immunoreactivity, whereas P2 and P3 were accompanied by protein dislocation. P1 was accompanied by β-catenin membrane expression, while P2 and P3 exhibited β-catenin nuclear translocation. Primary BC samples expressed MEF2C in mammary ducts and scattered cells in the parenchyma. MEF2C emerges as a player in BCBM associated with disease severity and VEGFR-2 and β-catenin signaling.