Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice

The cyclooxygenase (COX)-2 gene encodes an inducible prostaglandin synthase enzyme that is overexpressed in adenocarcinomas and other tumors, Deletion of the murine Cox-2 gene in Min mice reduced the incidence of intestinal t umors, suggesting that it is required for tumorigenesis, However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic trans formation. We have derived transgenic mice that overexpress the human COX-2 gene in the mammary glands using the murine mammary tumor virus promoter. The human Cox-2 mRNA and protein are expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. F emale virgin Cox-2 transgenic mice showed precocious lobuloalveolar differe ntiation and enhanced expression of the beta -casein gene, which was inhibi ted by the Cox inhibitor indomethacin, Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epi thelial cells. Multiparous but not virgin females exhibited a greatly exagg erated incidence of focal mammary gland hyperplasia, dysplasia, and transfo rmation into metastatic tumors. Cox-2-induced tumor tissue expressed reduce d levels of the proapoptotic proteins Bax and Bcl-X-L and an increase in th e anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mamm ary epithelial cells contributes to tumorigenesis, These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigene sis, Therefore, inhibition of Cox-2 may represent a mechanism-based chemopr eventive approach for carcinogenesis.