title: Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis.
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.
authors.affiliation: 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.
authors.forename: Helong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Ahirwar
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Oghumu
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Wilkie
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.affiliation: School of Medicine and Eccles Institute of Human Genetics, The University of Utah, USA.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, USA. Electronic address: Ramesh.Ganju@osumc.edu.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse; C516025:SecinH3; C569043:Tjp1 protein, mouse; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse
keywords: Angiogenesis; Breast cancer; Robo4; Tight junction; ZO-1