Transcription of Cyclooxygenase-2 Is Enhanced in Transformed Mammary Epithelial Cells1

Cancers form more prostaglandins than the normal tissues from which they arise. Cyclooxygenase-2 (prostaglandin H synthase-2, PGHS-2, EC 1.14.99.1), an enzyme that catalyzes the formation of prostaglandins from arachidonic acid, is inducible in epithelial cells. We investigated whether transformation of mammary cells was associated with up-regulation of Cox-2 as a basis for increased production of prostaglandin !'._,(PGE2) by these cells. This hypothesis was tested in two pairs of mammary cell lines between which the mode of transformation (viral versus oncogene) dif fered. Virali) transformed Rlll/Prl cells, which are highly tumorigenic in mice, produced markedly increased amounts of PGE, compared to virally initiated Kill/Ml, cells, a weakly tumorigenic strain. Cox-2 mRNA and protein were increased concomitantly in RHI/Prl cells. Similarly, Rasinduced transformation of C57/MG cells resulted in increased levels of Cox-2 mRNA and protein and increased production of PGE2. Nuclear imi-oil's revealed increased rates of Cox-2 transcription in the virally transformed and oncogene-transformed cell lines. Transient transfection experiments demonstrated that the oncogenes src and ras up-regulated Cox-2 promoter activity. Src-mediated up-regulation of Cox-2 promoter activity was suppressed by dominant negative ras. Our data indicate that cellular transformation is associated with enhanced transcription of Cox-2 and increased production of PGE2.