title: PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.
abstract: The molecular mechanisms that enable cyclooxygenase-2 (COX-2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor-beta (TGF-beta) signaling during mammary tumorigenesis remain unknown. We show here that TGF-beta selectively stimulated the expression of the PGE2 receptor EP2, which increased normal and malignant mammary epithelial cell (MEC) invasion, anchorage-independent growth, and resistance to TGF-beta-induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF-beta to Smad2/3 activation and plasminogen activator inhibitor-1 (PAI1) expression, while EP2 deficiency in these same MECs augmented Smad2/3 activation and PAI expression stimulated by TGF-beta. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF-beta, decreased their invasiveness in response to TGF-beta, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF-beta. More important, we show that COX-2 or EP2 deficiency both significantly decreased the growth, angiogenesis, and pulmonary metastasis of mammary tumors produced in mice. Collectively, this investigation establishes EP2 as a potent mediator of the anti-TGF-beta activities elicited by COX-2/PGE2 in normal and malignant MECs. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the oncogenic activities of TGF-beta during mammary tumorigenesis.-Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.
authors.affiliation: Department of Pharmacology, MS-8303, University of Colorado Denver, Anschutz Medical Campus, RC1 South Tower, Rm. L18-6110, 12801 East 17th Ave., PO Box 6511, Aurora, CO 80045, USA.
authors.forename: Maozhen
authors.initials: M
authors.lastname: Tian
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D017395:Plasminogen Activator Inhibitor 1; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2