COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer

Br J Cancer. 2006 Apr 24;94(8):1154-63. doi: 10.1038/sj.bjc.6603067.


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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / physiology*
  • Cyclooxygenase Inhibitors / pharmacology
  • Down-Regulation
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Female
  • Glycoproteins / biosynthesis
  • Humans
  • Imidazoles / pharmacology
  • Lymphangiogenesis / physiology*
  • Molecular Sequence Data
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E / physiology
  • Receptors, Prostaglandin E, EP1 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors
  • Vascular Endothelial Growth Factor C / biosynthesis
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vesicular Transport Proteins


  • 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
  • Cyclooxygenase Inhibitors
  • Glycoproteins
  • Imidazoles
  • LYVE1 protein, human
  • PTGER1 protein, human
  • PTGER4 protein, human
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Quinazolines
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP1 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Vascular Endothelial Growth Factor C
  • Vesicular Transport Proteins
  • Cyclooxygenase 2
  • SB 203580
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline

Associated data

  • GENBANK/AF118108
  • GENBANK/AF261085
  • RefSeq/NM_000963
  • RefSeq/NM_003376
  • RefSeq/NM_003377
  • RefSeq/NM_004469
  • RefSeq/NM_005429