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Mol Oncol. 2016 Feb;10(2):272-81. doi: 10.1016/j.molonc.2015.10.007. Epub 2015 Oct 28.

Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.

Author information

1
Department of Pathology, The Ohio State University Wexner Medical Center, USA; School of Medicine and Eccles Institute of Human Genetics, The University of Utah, USA.
2
Department of Pathology, The Ohio State University Wexner Medical Center, USA.
3
School of Medicine and Eccles Institute of Human Genetics, The University of Utah, USA.
4
Department of Pathology, The Ohio State University Wexner Medical Center, USA. Electronic address: Ramesh.Ganju@osumc.edu.

Abstract

Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein-1 (ZO-1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.

KEYWORDS:

Angiogenesis; Breast cancer; Robo4; Tight junction; ZO-1

PMID:
26778715
PMCID:
PMC4739522
DOI:
10.1016/j.molonc.2015.10.007
[Indexed for MEDLINE]
Free PMC Article

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