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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 tumors, suggesting that it is required for tumorigenesis. However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic transformation. 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. Female virgin Cox-2 transgenic mice showed precocious lobuloalveolar differentiation and enhanced expression of the beta-casein gene, which was inhibited by the Cox inhibitor indomethacin. Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epithelial cells. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. Cox-2-induced tumor tissue expressed reduced levels of the proapoptotic proteins Bax and Bcl-x(L) and an increase in the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigenesis. Therefore, inhibition of Cox-2 may represent a mechanism-based chemopreventive approach for carcinogenesis.

Pubmed ID: 11278747

Authors

  • Liu CH
  • Chang SH
  • Narko K
  • Trifan OC
  • Wu MT
  • Smith E
  • Haudenschild C
  • Lane TF
  • Hla T

Journal

The Journal of biological chemistry

Publication Data

May 25, 2001

Associated Grants

None

Mesh Terms

  • Animals
  • Cyclooxygenase 2
  • Female
  • Gene Expression Regulation, Enzymologic
  • Isoenzymes
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Transgenic
  • Prostaglandin-Endoperoxide Synthases