ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells

Oncogene. 2018 Feb 22;37(8):1005-1019. doi: 10.1038/onc.2017.356. Epub 2017 Oct 30.


During normal tumor growth and in response to some therapies, tumor cells experience acute or chronic deprivation of nutrients and oxygen and induce tumor vascularization. While this occurs predominately through sprouting angiogenesis, tumor cells have also been shown to directly contribute to vessel formation through vascular mimicry (VM) and/or endothelial transdifferentiation. The extrinsic and intrinsic mechanisms underlying tumor cell adoption of endothelial phenotypes, however, are not well understood. Here we show that serum withdrawal induces mesenchymal breast cancer cells to undergo VM and that knockdown of the epithelial-to-mesenchymal transition (EMT) regulator, Zinc finger E-box binding homeobox 1 (ZEB1), or overexpression of the ZEB1-repressed microRNAs (miRNAs), miR-200c, miR-183, miR-96 and miR-182 inhibits this process. We find that secreted proteins Fibronectin 1 (FN1) and serine protease inhibitor (serpin) family E member 2 (SERPINE2) are essential for VM in this system. These secreted factors are upregulated in mesenchymal cells in response to serum withdrawal, and overexpression of VM-inhibiting miRNAs abrogates this upregulation. Intriguingly, the receptors for these secreted proteins, low-density lipoprotein receptor-related protein 1 (LRP1) and Integrin beta 1 (ITGB1), are also targets of the VM-inhibiting miRNAs, suggesting that autocrine signaling stimulating VM is regulated by ZEB1-repressed miRNA clusters. Together, these data provide mechanistic insight into the regulation of VM and suggest that miRNAs repressed during EMT, in addition to suppressing migratory and stem-like properties of tumor cells, also inhibit endothelial phenotypes of breast cancer cells adopted in response to a nutrient-deficient microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autocrine Communication*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / blood supply*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Movement
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • MicroRNAs / genetics*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology*
  • Prognosis
  • Serpin E2 / genetics
  • Serpin E2 / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*


  • Biomarkers, Tumor
  • MicroRNAs
  • Serpin E2
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1