title: Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.
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 TGFbeta signaling pathway were induced by RA, and specific inhibition of the TGFbeta type I receptor 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.
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C., United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Prahalad
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Habtom
authors.initials: H
authors.lastname: Ressom
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D000970:Antineoplastic Agents; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D051837:COUP Transcription Factor II / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D051837:COUP Transcription Factor II; D015820:Cadherins; D018125:Receptors, Transforming Growth Factor beta; D014212:Tretinoin; D000099152:Cadherin 5
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