Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.
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.
Prahalad
Priya
P
Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C., United States of America.
Dakshanamurthy
Sivanesan
S
Ressom
Habtom
H
Byers
Stephen W
SW
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
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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