NHERF1 and tumor microenvironment: a new scene in invasive breast carcinoma

Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de-regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na /H exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported. Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF-1α), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions. Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1α (p = 0.021) and TWIST1 (p = 0.001). Further, immunofluorescence revealed an involvement of tumor cells with NHERF1 positive staining in neo-vascular formation, suggesting a "mosaic" structure development of these neo-vessels. Survival analyses showed that loss of nuclear TWIST1 (nTWIST1) expression was related to a decrease of disease free survival (DFS) (p