Cyclooxygenase (COX), also referred to as prostaglandin endoperoxide synthase, is the rate-limiting enzyme for the metabolic conversion of arachidonic acid to prostaglandins (PGs) and related eicosanoids. Some human breast cancers synthesize large quantities of PGE2, but the regulatory mechanisms involved are unclear. We have examined the expression of the two isoforms of this enzyme, COX-1 and COX-2, their regulation by tetradecanoyl phorbol acetate (TPA), and the associated PGE2 production in two human breast cancer cell lines with different biological phenotypes. Estrogen-dependent MCF-7 cells exhibited a relatively high expression of COX-1; COX-2 was barely detectable but was transiently induced by treatment with TPA (10 nm). In contrast, the estrogen-independent, highly invasive, metastatic MDA-MB-231 cell line showed a low expression of COX-1 but a high constitutive level of COX-2. This high COX-2 expression applied to both the protein and mRNA and increased further over a relatively long period of time in the presence of TPA. The extent of PGE2 production by the two cell lines correlated well with the level of COX-2 protein, suggesting that this isoform is required for both their constitutive and mitogen-induced PGE2 synthesis. Moreover, over-expression and persistent expression of COX-2 may be influenced by breast tumor hormone status and seem to be a feature of the aggressive, metastatic phenotype.

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Supported by Grant 94A12 from the American Institute for Cancer Research.

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