TRANSCRIPTION OF CYCLOOXYGENASE-2 IS ENHANCED IN TRANSFORMED MAMMARY EPITHELIAL-CELLS

Cancers form more prostaglandins than the normal tissues from which th ey arise. Cyclooxygenase-2 (prostaglandin H synthase-2, PGHS-2, EC 1.1 4.99.1), an enzyme that catalyzes the formation of prostaglandins from arachidonic acid, is inducible In epithelial cells. We investigated w hether transformation of mammary cells was associated with up-regulati on of Cox-2 as a basis for increased production of prostaglandin E(2) (PGE(2)) by these cells. This hypothesis was tested in two pairs of ma mmary cell lines between which the mode of transformation (viral versu s oncogene) differed. Virally transformed RIII/Pr1 cells, which are hi ghly tumorigenic in mice, produced markedly increased amounts of PGE(2 ) compared to virally initiated RIII/MG cells, a weakly tumorigenic st rain, Cox-2 mRNA and protein were increased concomitantly in RIII/Pr1 cells. Similarly, Ras-induced transformation of C57/MG cells resulted in increased levels of Cox-2 mRNA and protein and increased production of PGE(2). Nuclear run-offs revealed increased rates of Cox-2 transcr iption in the virally transformed and oncogene-transformed cell lines. Transient transfection experiments demonstrated that the oncogenes sr c and ras up-regulated Cox-2 promoter activity. Src-mediated up-regula tion of Cox-2 promoter activity was suppressed by dominant negative ra s. Our data indicate that cellular transformation is associated with e nhanced transcription of Cox-2 and increased production of PGE(2).