retinoic acid mediates regulation of network formation by coup-tfii and ve-cadherin expression by tgfβ receptor kinase in breast cancer cells视黄酸介导的监管网络形成coup-tfii和ve-cadherin tgfβ受体激酶表达的乳腺癌细胞.pdfVIP

Retinoic Acid Mediates Regulation of Network Formation by COUP-TFII and VE-Cadherin Expression by TGFb Receptor Kinase in Breast Cancer Cells Priya Prahalad, Sivanesan Dakshanamurthy, Habtom Ressom, Stephen W. Byers* Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C., United States of America Abstract 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, 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 TGFb signaling pathway were induced by RA, and specific inhibition of the TGF b type I receptor blocked both RA-induced VE-cadherin expression and cell fusion. Together these data indicate a role for the TGFb pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA. Citation: Prahalad P, Dakshanamurthy S, Ressom H, Byers SW (2010) Retin