Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms.
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.
Neil
Jason R
JR
Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Johnson
Kyle M
KM
Nemenoff
Raphael A
RA
Schiemann
William P
WP
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; D015232:Dinoprostone