Overexpression of Cyclooxygenase-2 Is Sufficient to Induce Tumorigenesis in Transgenic Mice*
By Catherine H. Liu, Sung-Hee Chang, K. Narko, O. Trifan, Ming-Tao Wu, Elizabeth Smith, C. Haudenschild, T. Lane, T. Hla. Journal of Biological Chemistry, 2001
865 citations recorded by the source corpus.
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 inMin 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 β-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-xL 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.
Subfields: Genetics, Pharmacology, Psychiatry and Mental health
View Paper: https://www.semanticscholar.org/paper/6c621b61e139de96994da8aa6b04d3abee1ab968
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In Pharmacology
Citations in the corpus
- Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition (2004, background): “These data suggest that ectopic overexpression of COX-2 gene is sufficient to transform the mammary gland after repeated cycles of pregnancy and lactation (Liu et al., 2001).”
- Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 (2001, background): “A study by Liu et al.28 was the first to show that overexpression of Cox2 alone is sufficient to induce cellular transformation.”
- The Role of COX-2 in Intestinal Inflammation and Colorectal Cancer (2009, neutral): “Although the data that overexpression of COX-2 initiates colorectal carcinogenesis in transgenic mouse models have not been reported, overexpression of COX-2 in transgenic mice using a murine mammary tumor virus promoter induced breast carcinoma formation (Liu et al., 2001).”
- Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. (2002, background): “3), and because expression of Cox-2 as such was sufficient for formation of breast tumors in transgenic mice (7).”
- IL‐1β mediated up‐regulation of HIF‐lα via an NFkB/COX‐2 pathway identifies HIF‐1 as a critical link between inflammation and oncogenesis (2003, background): “Moreover, overexpression of COX-2 is involved in the metastatic transformation of tumors (22).”