Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells

Louise R. Howe, Kotha Subbaramaiah, Wen Jing Chung, Andrew J. Dannenberg, Anthony M.C. Brown

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

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 β-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 β-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 β-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 Writ-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.

Original languageEnglish (US)
Pages (from-to)1572-1577
Number of pages6
JournalCancer research
Volume59
Issue number7
StatePublished - Apr 1 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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