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PMID: 19897661 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology ·Vol. 24 ·No. 4 ·2010-04-00 ·Pages 1105-16

Tian M, Schiemann WP

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.

MeSH Terms
Animals Cell Line, Tumor Cell Transformation, Neoplastic/metabolism,pathology Cyclooxygenase 2/metabolism Female Gene Expression Regulation, Neoplastic Mammary Neoplasms, Animal/metabolism,pathology Mice Mice, Inbred BALB C Neoplasm Invasiveness Neoplasm Proteins/metabolism Plasminogen Activator Inhibitor 1/biosynthesis Receptors, Prostaglandin E/antagonists & inhibitors,biosynthesis Receptors, Prostaglandin E, EP2 Subtype Signal Transduction Smad2 Protein/metabolism Smad3 Protein/metabolism Transforming Growth Factor beta/metabolism
Chemicals
Neoplasm Proteins Plasminogen Activator Inhibitor 1 Ptger2 protein, mouse Receptors, Prostaglandin E Receptors, Prostaglandin E, EP2 Subtype Smad2 Protein Smad2 protein, mouse Smad3 Protein Smad3 protein, mouse Transforming Growth Factor beta Ptgs2 protein, mouse Cyclooxygenase 2
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Tian Maozhen
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.
Schiemann William P
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Article Info
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Abbr.
FASEB J
ISSN
1530-6860
DOI
10.1096/fj.09-141341
Published
2010-04-00
Epub
2009-00-06
Pages
1105-16
Language
English
Region
United States
NLM ID
8804484
PMCID
PMC2845432
Subset
IM
Grants
NCI NIH HHS · R01 CA114039 · United States
NCI NIH HHS · R01 CA129359 · United States
NCI NIH HHS · CA-129359 · United States
NCI NIH HHS · CA-114039 · United States
External Links
PubMed source DOI: 10.1096/fj.09-141341 PMC Full Text View journal details
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