The study investigates the role of cyclooxygenase-2 (COX-2) in tumorigenesis using transgenic mice that overexpress the human COX-2 gene in the mammary glands. The COX-2 gene, which encodes an inducible prostaglandin synthase enzyme, is overexpressed in various types of tumors. The researchers derived transgenic mice using the murine mammary tumor virus promoter, which induced high levels of COX-2 expression in the mammary glands, particularly during pregnancy and lactation. Virgin COX-2 transgenic mice exhibited precocious lobuloalveolar differentiation and enhanced expression of the β-casein gene, which was inhibited by the COX inhibitor indomethacin. The COX-2 transgenic mice also showed delayed mammary gland involution and decreased apoptotic index of mammary epithelial cells. Multiparous females exhibited a significantly higher incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. The tumors expressed reduced levels of proapoptotic proteins Bax and Bcl-xL and increased levels of the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis contributes to tumorigenesis. These findings indicate that enhanced COX-2 expression is sufficient to induce mammary gland tumorigenesis, providing evidence for a mechanism-based chemopreventive approach to inhibit carcinogenesis.The study investigates the role of cyclooxygenase-2 (COX-2) in tumorigenesis using transgenic mice that overexpress the human COX-2 gene in the mammary glands. The COX-2 gene, which encodes an inducible prostaglandin synthase enzyme, is overexpressed in various types of tumors. The researchers derived transgenic mice using the murine mammary tumor virus promoter, which induced high levels of COX-2 expression in the mammary glands, particularly during pregnancy and lactation. Virgin COX-2 transgenic mice exhibited precocious lobuloalveolar differentiation and enhanced expression of the β-casein gene, which was inhibited by the COX inhibitor indomethacin. The COX-2 transgenic mice also showed delayed mammary gland involution and decreased apoptotic index of mammary epithelial cells. Multiparous females exhibited a significantly higher incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. The tumors expressed reduced levels of proapoptotic proteins Bax and Bcl-xL and increased levels of the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis contributes to tumorigenesis. These findings indicate that enhanced COX-2 expression is sufficient to induce mammary gland tumorigenesis, providing evidence for a mechanism-based chemopreventive approach to inhibit carcinogenesis.