Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: Evidence for involvement of AP-1 and PEA3 Journal Article
| Authors: | Subbaramaiah, K.; Norton, L.; Gerald, W.; Dannenberg, A. J. |
| Article Title: | Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: Evidence for involvement of AP-1 and PEA3 |
| Abstract: | 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. |
| Keywords: | immunohistochemistry; signal transduction; mitogen activated protein kinase; controlled study; unclassified drug; human cell; promoter region; raf protein; nonhuman; animal cell; mouse; gene overexpression; breast cancer; gene expression; membrane proteins; breast neoplasms; animalia; transcription factors; gene expression regulation, neoplastic; transcription regulation; tumors; cyclooxygenase 2; prostaglandin e2; epithelial cells; base sequence; ras protein; gene induction; dna primers; biochemistry; genes, erbb-2; mutagenesis; enzymes; isoenzymes; cell lysate; gene expression regulation, enzymologic; cells; neu differentiation factor; transcription factor ap 1; transcription factor ap-1; prostaglandin-endoperoxide synthases; humans; human; priority journal; article; transcription factor pea3; cyclic amp responsive element |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 277 |
| Issue: | 21 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2002-05-24 |
| Start Page: | 18649 |
| End Page: | 18657 |
| Language: | English |
| DOI: | 10.1074/jbc.M111415200 |
| PUBMED: | 11901151 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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