title: Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression.
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.
authors.affiliation: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Liu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Conway
authors.forename: David K
authors.initials: DK
authors.lastname: Han
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Trifan
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Lane
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D018450:Disease Progression; D007527:Isoenzymes / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone