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      Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms.

      Carcinogenesis
      Animals, Cyclooxygenase 2, metabolism, Dinoprostone, physiology, Epithelial Cells, cytology, Mesoderm, Mice, Signal Transduction, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta

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          Abstract

          Although it is well established that mammary tumorigenesis converts transforming growth factor-beta (TGF-beta) from a tumor suppressor to a tumor promoter, the molecular, cellular and microenvironmental mechanisms underlying the dichotomous nature of TGF-beta 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-beta remains unknown. We show here that TGF-beta 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-beta. Conversely, antagonizing TGF-beta signaling in malignant, metastatic MECs significantly reduced their expression of Cox-2 as well as enhanced their activation of Smad2/3 by TGF-beta. Along these lines, elevated Cox-2 expression elicited prostaglandin E(2) (PGE(2)) 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 PGE(2) 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-beta in malignant, metastatic breast cancers.

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          Author and article information

          Journal
          18725385
          2577139
          10.1093/carcin/bgn202

          Chemistry
          Animals,Cyclooxygenase 2,metabolism,Dinoprostone,physiology,Epithelial Cells,cytology,Mesoderm,Mice,Signal Transduction,Smad2 Protein,Smad3 Protein,Transforming Growth Factor beta

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