Abstract
Increased expression of COX-2 or VEGF-C has been correlated with progressive disease in certain cancers. Present study utilized several human breast cancer cell lines (MCF-7, T-47D, Hs578T and MDA-MB-231, varying in COX-2 expression) as well as 10 human breast cancer specimens to examine the roles of COX-2 and prostaglandin E (EP) receptors in VEGF-C expression or secretion, and the relationship of COX-2 or VEGF-C expression to lymphangiogenesis. We found a strong correlation between COX-2 mRNA expression and VEGF-C expression or secretion levels in breast cancer cell lines and VEGF-C expression in breast cancer tissues. Expression of LYVE-1, a selective marker for lymphatic endothelium, was also positively correlated with COX-2 or VEGF-C expression in breast cancer tissues. Inhibition of VEGF-C expression and secretion in the presence of COX-1/2 or COX-2 inhibitors or following downregulation of COX-2 with COX-2 siRNA established a stimulatory role COX-2 in VEGF-C synthesis by breast cancer cells. EP1 as well as EP4 receptor antagonists inhibited VEGF-C production indicating the roles of EP1 and EP4 in VEGF-C upregulation by endogenous PGE2. Finally, VEGF-C secretion by MDA-MB-231 cells was inhibited in the presence of kinase inhibitors for Her-2/neu, Src and p38 MAPK, indicating a requirement of these kinases for VEGF-C synthesis. These results, for the first time, demonstrate a regulatory role of COX-2 in VEGF-C synthesis (and thereby lymphangiogenesis) in human breast cancer, which is mediated at least in part by EP1/EP4 receptors.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Cyclooxygenase 2 / biosynthesis
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Cyclooxygenase 2 / drug effects
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Cyclooxygenase 2 / physiology*
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Cyclooxygenase Inhibitors / pharmacology
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Down-Regulation
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Female
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Glycoproteins / biosynthesis
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Humans
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Imidazoles / pharmacology
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Lymphangiogenesis / physiology*
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Molecular Sequence Data
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Quinazolines / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Prostaglandin E / metabolism
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Receptors, Prostaglandin E / physiology
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Receptors, Prostaglandin E, EP1 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor C / antagonists & inhibitors
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Vascular Endothelial Growth Factor C / biosynthesis
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Vascular Endothelial Growth Factor C / metabolism*
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Vesicular Transport Proteins
Substances
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4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
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Cyclooxygenase Inhibitors
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Glycoproteins
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Imidazoles
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LYVE1 protein, human
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PTGER1 protein, human
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PTGER4 protein, human
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Pyrazoles
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Pyridines
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Pyrimidines
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Quinazolines
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP1 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Vascular Endothelial Growth Factor C
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Vesicular Transport Proteins
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Cyclooxygenase 2
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SB 203580
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4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
Associated data
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GENBANK/AF118108
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GENBANK/AF261085
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RefSeq/NM_000963
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RefSeq/NM_003376
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RefSeq/NM_003377
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RefSeq/NM_004469
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RefSeq/NM_005429