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Differential Expression and Regulation of Cyclooxygenase-1 and -2 in Two Human Breast Cancer Cell Lines¹

Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, New York 10595

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.

¹ Supported by Grant 94A12 from the American Institute for Cancer Research.

² To whom requests for reprints should be addressed, at the Division of Nutrition and Endocrinology, American Health Foundation, 1 Dana Road, Valhalla, NY 10595.

Received 8/30/95. Accepted 10/ 1/96.

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