Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: Evidence for involvement of AP-1 and PEA3

Kotha Subbaramaiah, Larry Norton, William Gerald, Andrew J. Dannenberg

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311 Scopus citations


Markedly increased levels of cyclooxygenase-2 (COX-2) mRNA, protein, and prostaglandin E2 synthesis were detected in HER-2/neu-transformed human mammary epithelial cells (184B5/HER) compared with its nontransformed partner cell line (184B5). HER-2/neu stimulated COX-2 transcription via the Ras → Raf → MAPK pathway. The inductive effects of HER-2/neu were mediated, in part, by enhanced binding of AP-1 (c-Jun, c-Fos, and ATF-2) to the cyclic AMP-response element (-59/-53) of the COX-2 promoter. The potential contribution of the transcription factor PEA3 was also investigated. Elevated levels of PEA3 were detected in 184B5/HER cells. A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element. HER-2/neu-mediated activation of the COX-2 promoter was blocked by mutagenizing the PEA3 site or overexpressing antisense to PEA3. To determine whether HER-2/neu status was also a determinant of COX-2 expression in vivo, we compared levels of COX-2 protein in HER-2/neu-positive and -negative human breast cancers. Increased amounts of COX-2 were detected in HER-2/neu-positive tumors. Taken together, these results suggest that closely spaced PEA3 and cyclic AMP-response elements are required for HER-2/neu-mediated induction of COX-2 transcription. The clear relationship between HER-2/neu status and COX-2 expression in human breast tumors suggests that this mechanism is likely to be operative in vivo.

Original languageEnglish (US)
Pages (from-to)18649-18657
Number of pages9
JournalJournal of Biological Chemistry
Issue number21
StatePublished - May 24 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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