Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells.
Wnt-1 acts as a mammary oncogene when ectopically expressed in the mouse mammary gland. APC is a tumor suppressor gene, mutations in which cause intestinal tumorigenesis in humans and rodents. Both Wnt-1 expression and APC mutation activate a common signaling pathway involving transcriptional activation mediated by beta-catenin/Tcf complexes, but few targets relevant to carcinogenesis have yet been identified. Expression of the inducible prostaglandin synthase cyclooxygenase-2 appears critical for intestinal tumorigenesis resulting from APC mutation, suggesting that cyclooxygenase-2 might be a transcriptional target for beta-catenin/Tcf complexes. Here, we have investigated the effect of Wnt-1 on cyclooxygenase-2 expression. Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG induces stabilization of cytosolic beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the cyclooxygenase-2 gene, resulting in increased levels of cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated cyclooxygenase-2 activity and could be decreased by treatment with a selective cyclooxygenase-2 inhibitor. Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and Wnt-1 expression. In view of the critical role of cyclooxygenase-2 in intestinal tumorigenesis, cyclooxygenase-2 up-regulation in response to Wnt signaling may contribute to Wnt-induced mammary carcinogenesis.
Howe
L R
LR
Strang Cancer Research Laboratory, The Rockefeller University, New York, New York 10021, USA.
Subbaramaiah
K
K
Chung
W J
WJ
Dannenberg
A J
AJ
Brown
A M
AM
D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells; D005260:Female; D007527:Isoenzymes / Q000235:genetics*; D008321:Mammary Glands, Animal; D051379:Mice; D009857:Oncogenes; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone