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

Overview

MeSH Major

  • Breast Neoplasms
  • Genes, erbB-2
  • Isoenzymes
  • Prostaglandin-Endoperoxide Synthases
  • Transcription Factor AP-1
  • Transcription Factors

abstract

  • Markedly increased levels of cyclooxygenase-2 (COX-2) mRNA, protein, and prostaglandin E(2) 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.

publication date

  • May 24, 2002

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111415200

PubMed ID

  • 11901151

Additional Document Info

start page

  • 18649

end page

  • 57

volume

  • 277

number

  • 21