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

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

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Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Department of Pathology & Immunology, Washington University, St. Louis, MO, USA.
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.


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.

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