Faculty Collaboration Database

Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A 2004 Jan 13;101(2):591-6

Date

12/23/2003

Pubmed ID

14688410

Pubmed Central ID

PMC327192

DOI

10.1073/pnas.2535911100

Scopus ID

2-s2.0-0347717578 (requires institutional sign-in at Scopus site)   363 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 E(2) (PGE(2)) EP(1-4), are expressed during mammary gland development, and EP(1,2,4) receptors were up-regulated in tumor tissue. PGE(2) 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 PGE(2) as a potent inducer of angiogenic switch during mammary cancer progression.

Author List

Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T

MESH terms used to index this publication - Major topics in bold

Animals
Chromatography, Liquid
Cyclooxygenase 2
Dinoprostone
Disease Progression
Isoenzymes
Mammary Neoplasms, Experimental
Mice
Mice, Nude
Neovascularization, Pathologic
Prostaglandin-Endoperoxide Synthases
Spectrometry, Mass, Electrospray Ionization