Ephrin‑B2 inhibits cell proliferation and motility in�vitro and predicts longer metastasis‑free survival in breast cancer

Abstract

The tyrosine kinase receptor EphB4 and its ligand ephrin-B2 interact through cell-to-cell contacts. Upon interaction, EphB4 transmits bidirectional signals. A forward signal inside EphB4-expressing cells is believed to suppress tumor growth, while inside the ephrin-expressing cells, an oncogenic reverse signal arises. In breast cancer cells with a high EphB4 receptor expression the forward signal is low, in part due to the low expression of the ligand ephrin-B2. Therefore, we hypothesized that by re-introducing the ligand in EphB4-positive cells, tumor suppression could be induced by the stimulation of the forward signal. This question was addressed in vitro by the stable lentiviral infection of breast cancer cells with either wild-type EFNB2 or with a mutant EFNB2-5F, unable to transmit reverse signaling. Furthermore, we investigated ephrin-B and EphB4 protein expression in 216 paraffin-embedded tumors using immunohistochemistry. The in vitro results indicated that ephrin-B2 expression was associated with a lower cell proliferation, migration and motility compared with the control cells. These effects were more pronounced when the cells lacked the ability to transmit the reverse signal (B2-5F). In clinical material, ephrin-B protein expression was associated with a positive estrogen receptor (ER) status, a low HER-2 expression and was negatively associated with Nottingham histologic grade (NHG) III. Ephrin-B expression indicated a good prognosis, whereas EphB4 expression was associated with a shorter metastasis-free survival in univariate and multivariate analysis. Furthermore, the prognostic value of EFNB2 and EPHB4 was confirmed at the gene expression level in public datasets. Thus, on the whole, the findings of this study suggest that ephrin-B2 expression is associated with less proliferation and lower motility of breast cancer cells and with a longer patient survival in breast cancer.

miR-193a-3p Mediates Placenta Accreta Spectrum Development by Targeting EFNB2 via Epithelial-Mesenchymal Transition Pathway Under Decidua Defect Conditions

“…However, how the EFNB2 induces EMT was unknown. EFNB2 repression induced tumor migration and invasion in human gliomas and breast cancer, which was similar to our results (Depner et al, 2016 ; Magic et al, 2019 ). In contrast, prior work determined that a decrease in EFNB2 levels impaired the migration/invasion capabilities of HTR-8/SVneo cells (Luo et al, 2015 ).…”

The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread

“…The established, immense impact of breast tumors' molecular signature in disease prognosis and treatment regimens has shifted the focus of the scientific community on those molecular mechanisms implicated in the disease pathogenesis and the search for novel biomarkers that influence the clinical outcome. Among them, the expression and effect of the EPH/ephrin system in breast cancer tumorigenesis has been extensively studied, with overexpression of all members contributing to worse disease prognosis [27][28][29][30][31][32][33][34].…”

Short-Form Thymic Stromal Lymphopoietin (sfTSLP) Is the Predominant Isoform Expressed by Gynaecologic Cancers and Promotes Tumour Growth

“…EFNB2 interacts with its receptor EphB4 through cell-to-cell contact. A recent report by Magic et al indicated that the introduction of wild-type EFNB2 in breast cancer cells in vitro using stable lentiviral infection was associated with lower cell proliferation, migration and motility compared to controls; in clinical breast cancer specimens, EFNB2 expression was associated with longer patient survival [ 48 ]. Based on this information, we hypothesised that the overexpression of sfTSLP promotes tumour growth through the downregulation of EFNB2.…”