Carcinogenesis Advance Access originally published online on August 25, 2008
Carcinogenesis 2008 29(11):2227-2235; 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 mechanisms
1 Department of Pharmacology
2 Department of Medicine, University of Colorado Health Sciences Center, Aurora, CO 80045, USA
* To whom correspondence should be addressed. Department of Pharmacology, University of Colorado Health Sciences Center, RC1 South Tower, Room L18-6110, 12801 East 17th Avenue, PO Box 6511, Aurora, CO 80045, USA. Tel: +1 303 724 1541; Fax: +1 303 724 3663; Email: bill.schiemann{at}uchsc.edu
Although it is well established that mammary tumorigenesis converts transforming growth factor-β (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 prostaglandin E2 (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 plasminogen activator inhibitor-1 and p15 messenger RNA. 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.
Abbreviations: Cox, cyclooxygenase; DCIS, ductal carcinoma in situ; EMT, epithelial–mesenchymal transition; ERK, extracellular signal-regulated kinase; GSK, glycogen synthase kinase; MAPK, mitogen-activated protein kinase; MEC, mammary epithelial cell; mRNA, messenger RNA; NF-
B, nuclear factor kappa B; PCR, polymerase chain reaction; PGE, prostaglandin E2; PI3K, phosphoinositide 3-kinase; SBE, smad-binding element; TGF-β, transforming growth factor-β; TβR-I, transforming growth factor-β type I
Received July 24, 2008; revised August 14, 2008; accepted August 18, 2008.
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