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

Helong Zhao, Dinesh K. Ahirwar, Steve Oghumu, Tasha Wilkie, Catherine A. Powell, Mohd W. Nasser, Abhay R. Satoskar, Dean Y. Li, Ramesh K. Ganju

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)272-281
Number of pages10
JournalMolecular Oncology
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Breast Neoplasms
Neoplasm Metastasis
Growth
Neoplasms
Zonula Occludens-1 Protein
Pathologic Neovascularization
Tight Junction Proteins
Hematopoietic Stem Cells
Knockout Mice
Pharmaceutical Preparations
Vascular Endothelial Growth Factor A
Arthritis
Shock
Sepsis
Down-Regulation
Cell Proliferation
SecinH3
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis. / Zhao, Helong; Ahirwar, Dinesh K.; Oghumu, Steve; Wilkie, Tasha; Powell, Catherine A.; Nasser, Mohd W.; Satoskar, Abhay R.; Li, Dean Y.; Ganju, Ramesh K.

In: Molecular Oncology, Vol. 10, No. 2, 01.02.2016, p. 272-281.

Research output: Contribution to journalArticle

Zhao, H, Ahirwar, DK, Oghumu, S, Wilkie, T, Powell, CA, Nasser, MW, Satoskar, AR, Li, DY & Ganju, RK 2016, 'Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis', Molecular Oncology, vol. 10, no. 2, pp. 272-281. https://doi.org/10.1016/j.molonc.2015.10.007
Zhao, Helong ; Ahirwar, Dinesh K. ; Oghumu, Steve ; Wilkie, Tasha ; Powell, Catherine A. ; Nasser, Mohd W. ; Satoskar, Abhay R. ; Li, Dean Y. ; Ganju, Ramesh K. / Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis. In: Molecular Oncology. 2016 ; Vol. 10, No. 2. pp. 272-281.
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