Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3.
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.
Subbaramaiah
Kotha
K
Department of Medicine, New York Presbyterian Hospital, Weill Medical College of Cornell University, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Norton
Larry
L
Gerald
William
W
Dannenberg
Andrew J
AJ
D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C065788:transcription factor PEA3; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases