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PGE2 receptor EP2 mediates the antagonistic effect of COX‐2 on TGF‐β signaling during mammary tumorigenesis
Author(s) -
Tian Maozhen,
Schiemann William P.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-141341
Subject(s) - cytostasis , transforming growth factor , prostaglandin e2 receptor , cancer research , carcinogenesis , signal transduction , mediator , mammary tumor , receptor , biology , endocrinology , medicine , chemistry , microbiology and biotechnology , cancer , agonist , biochemistry , in vitro , breast cancer , cytotoxicity
The molecular mechanisms that enable cyclooxygenase‐2 (COX‐2) and its mediator prostaglandin E2 (PGE2) to inhibit transforming growth factor‐β (TGF‐β) signaling during mammary tumorigenesis remain unknown. We show here that TGF‐β 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‐β‐induced cytostasis. Mechanistically, elevated EP2 expression in normal MECs inhibited the coupling of TGF‐β 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‐β. Along these lines, engineering malignant MECs to lack EP2 expression prevented their growth in soft agar, restored their cytostatic response to TGF‐β, decreased their invasiveness in response to TGF‐β, and potentiated their activation of Smad2/3 and expression of PAI stimulated by TGF‐β. 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‐β 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‐β during mammary tumorigenesis.—Tian, M., Schiemann, W. P. PGE2 receptor EP2 mediates the antagonistic effect of COX‐2 on TGF‐β signaling during mammary tumorigenesis. FASEB J. 24, 1105–1116 (2010). www.fasebj.org