Carcinogenesis Advance Access published online on August 25, 2008
Carcinogenesis, doi:10.1093/carcin/bgn202
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COX-2 Inactivates Smad Signaling and Enhances EMT Stimulated by TGF-β Through a PGE2-Dependent Mechanism
1 Department of Pharmacology University of Colorado Health Sciences Center, Aurora, Colorado 80045
2 Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado 80045
Corresponding Author: William P. Schiemann, Department of Pharmacology, University of Colorado Health Sciences Center, RC1 South Tower, Room L18-6110, 12801 East 17th Avenue, PO Box 6511, Aurora, Colorado 80045. Phone: (303)724-1541. Fax: (303)724-3663. Email: Bill.Schiemann{at}uchsc.edu
Although it is well established that mammary tumorigenesis converts TGF-β from a tumor suppressor to a tumor promoter, the molecular, cellular, and microenvironmental mechanisms underlying the dichotomous nature of TGF-β in mammary epithelial cells (MECs) remains to be determined definitively. Aberrant upregulation of the inducible cyclooxygenase, Cox-2, occurs frequently in breast cancers and is associated with increasing disease severity and the acquisition of metastasis; however, the impact of Cox-2 expression on normal and malignant MEC response to TGF-β remains unknown. We show here that TGF-β induced Cox-2 expression in normal MECs during their acquisition of an epithelial-mesenchymal transition (EMT) phenotype. Moreover, stable Cox-2 expression in normal MECs stimulated their invasion, EMT, and anchorage-independent growth, and inhibited their activation of Smad2/3 by TGF-β. Conversely, antagonizing TGF-β signaling in malignant, metastatic MECs significantly reduced their expression of Cox-2, as well as enhanced their activation of Smad2/3 by TGF-β. Along these lines, elevated Cox-2 expression elicited PGE2 production and the autocrine activation of EP receptors, which antagonized Smad2/3 signaling in normal and malignant MECs. Importantly, rendering normal and malignant MECs Cox-2-deficient inhibited their production of PGE2 and acquisition of an EMT morphology, as well as potentiated their nuclear accumulation of Smad2/3 and transcription of PAI-1 and p15 mRNA. Collectively, our findings establish Cox-2 as a novel antagonist of Smad2/3 signaling in normal and malignant MECs; they also suggest that chemotherapeutic targeting of Cox-2 may offer new inroads in restoring the tumor suppressing activities of TGF-β in malignant, metastatic breast cancers.
Key Words: Breast Cancer • Cox-2 • EMT • PGE2 • Smad • TGF-β
Received July 24, 2008; revised August 14, 2008; accepted August 18, 2008.
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