Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression

Sung Hee Chang, Catherine H. Liu, Rebecca Conway, David K. Han, Kasem Nithipatikom, Ovidiu C. Trifan, Timothy F Lane, Timothy Hla*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

322 Scopus citations

Abstract

Overexpression of human cyclooxygenase 2 (COX-2) in the mammary glands of transgenic mice induces tissue-specific tumorigenic transformation. However, the molecular mechanisms involved are not yet defined. Here we show that COX-2 expressed in the epithelial cell compartment regulates angiogenesis in the stromal tissues of the mammary gland. Microvessel density increased before visible tumor growth and exponentially during tumor progression. Inhibition of prostanoid synthesis with indomethacin strongly decreased microvessel density and inhibited tumor progression. Up-regulation of angiogenic regulatory genes in COX-2 transgenic mammary tissue was also potently inhibited by indomethacin treatment, suggesting that prostanoids released from COX-2-expressing mammary epithelial cells induce angiogenesis. G protein-coupled receptors for the major product, prostaglandin E2 (PGE2) EP1-4, are expressed during mammary gland development, and EP1,2,4 receptors were up-regulated in tumor tissue. PGE2 stimulated the expression angiogenic regulatory genes in mammary tumor cells isolated from COX-2 transgenic mice. Such cells are tumorigenic in nude mice; however, treatment with Celecoxib, a COX-2-specific inhibitor, reduced tumor growth and microvessel density. These results define COX-2-derived PGE2 as a potent inducer of angiogenic switch during mammary cancer progression.

Original languageEnglish (US)
Pages (from-to)591-596
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number2
DOIs
StatePublished - Jan 13 2004

Keywords

  • Mammary cancer
  • Prostaglandin E receptors
  • Tumor angiogenesis

ASJC Scopus subject areas

  • General

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