Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.

Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.

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Tumor development, growth, and metastasis depend on the provision of an adequate vascular supply.This can be due to regulated angiogenesis, recruitment of circulating endothelial progenitors, and/or vascular transdifferentiation.Our previous studies showed that retinoic acid (RA) treatment converts a subset of breast cancer cells into cells with significant endothelial genotypic and phenotypic elements including marked induction of VE-cadherin, Speed Controller which was responsible for some but not all morphological changes.The present study demonstrates that of the endothelial-related genes induced by RA treatment, only a few were affected by knockdown of VE-cadherin, ruling it out as a regulator of the RA-induced endothelial genotypic switch.In contrast, knockdown of the RA-induced gene COUP-TFII prevented the formation of networks in Matrigel but had no effect on VE-cadherin induction or cell fusion.

Two pan-kinase inhibitors markedly blocked RA-induced VE-cadherin expression and cell fusion.However, RA treatment resulted in a marked and broad reduction in tyrosine kinase activity.Several genes in the TGFbeta signaling pathway were induced by RA, and specific inhibition of the TGFbeta type I receptor Diffuser blocked both RA-induced VE-cadherin expression and cell fusion.Together these data indicate a role for the TGFbeta pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA.