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

• Published in: The Journal of biological chemistry Vol. 277; no. 21; pp. 18649 - 18657
• Main Authors: Subbaramaiah, Kotha, Norton, Larry, Gerald, William, Dannenberg, Andrew J
• Format: Journal Article
• Language: English
• Published: United States 24.05.2002
• Subjects: Base Sequence; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Cyclooxygenase 2; DNA Primers; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Isoenzymes - biosynthesis; Isoenzymes - genetics; Membrane Proteins; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - genetics; Transcription Factor AP-1 - metabolism; Transcription Factors - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M111415200

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.