NHERF1 and tumor microenvironment: a new scene in invasive breast carcinoma
Concetta Saponaro1, Alessandro Vagheggini2, Emanuela Scarpi2
1Functional Biomorphology Laboratory, IRCCS-Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy.
Background:
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.
Methods:
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.
Results:
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 < 0.001), while nTWIST1-/mNHERF1+ presented an increased DFS with respect to nTWIST1+/mNHERF1- phenotype (p < 0.001). Subsequently, the analyses of nTWIST1+/cNHERF1+ phenotype selected a subgroup of patients with a worse DFS compared to nTWIST1-/cNHERF1- patients (p = 0.004).
Conclusion:
Resulting data suggested a dynamic relation between NHERF1 and TME markers, and confirmed both the oncosuppressor role of membranous NHERF1 expression and the oncogene activity of cytoplasmic NHERF1.
Insights
The scaffolding protein NHERF1 influences breast cancer progression by interacting with tumor microenvironment (TME) factors. Cytoplasmic NHERF1 promotes cancer, while membranous NHERF1 acts as an oncosuppressor.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The tumor microenvironment (TME) significantly impacts cancer progression.
- The scaffolding protein NHERF1 has been implicated in breast cancer (BC) TME alterations.
Purpose of the Study:
- To investigate the relationship between NHERF1 subcellular localization and TME markers in breast cancer.
- To determine the prognostic significance of NHERF1 expression in relation to TME factors and patient survival.
Main Methods:
- Immunohistochemistry on tissue microarrays (TMA) for NHERF1, VEGF, VEGFR1, HIF-1α, TWIST1, and MVD in 183 invasive BCs.
- Immunofluorescence to analyze protein interactions and NHERF1's role in neovascularization.
- Survival analyses correlating NHERF1 expression patterns with disease-free survival (DFS).
Main Results:
- Cytoplasmic NHERF1 (cNHERF1) correlated with increased VEGF/VEGFR1 and decreased nuclear HIF-1α/TWIST1.
- NHERF1-positive tumor cells were involved in neo-vascular formation.
- Loss of nuclear TWIST1 (nTWIST1) and specific NHERF1/TWIST1 phenotypes significantly impacted DFS.
Conclusions:
- NHERF1 exhibits a dynamic relationship with TME markers in breast cancer.
- Membranous NHERF1 expression demonstrates an oncosuppressor role, whereas cytoplasmic NHERF1 displays oncogenic activity.
- NHERF1 localization is a critical factor in breast cancer progression and patient prognosis.
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