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Ephrin-B2 inhibits cell proliferation and motility in vitro and predicts longer metastasis-free survival in breast cancer
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 55, no 6, p. 1275-1286Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD , 2019. Vol. 55, no 6, p. 1275-1286
Keywords [en]
EFNB2; EphB4; bidirectional signaling; metastasis; receptor tyrosine kinase
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-162883DOI: 10.3892/ijo.2019.4892ISI: 000500272500008PubMedID: 31638179OAI: oai:DiVA.org:liu-162883DiVA, id: diva2:1382245
Note

Funding Agencies|Swedish Research CouncilSwedish Research Council [2009-7360]; Swedish Cancer SocietySwedish Cancer Society [160705]

Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-02-03

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Magic, ZeljanaSandström, JosefinePerez Tenorio, Gizeh
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