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Cyclooxygenase-1 Is Overexpressed in Multiple Genetically Engineered Mouse Models of Epithelial Ovarian Cancer

Departments of ¹ Pediatrics, ² Cell and Developmental Biology, and ³ Pharmacology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; ⁴ Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁵ Department of Biomedical Sciences, Cornell University, Ithaca, New York; and ⁶ Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Sudhansu K. Dey, Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: 615-322-8642; E-mail: sk.dey{at}vanderbilt.edu.

Cyclooxygenases-1 and -2 (Cox-1 and Cox-2) are two distinct isoforms that catalyze the conversion of arachidonic acid to prostaglandins. The role of Cox-2 in a variety of cancers is well recognized, but the contribution of Cox-1 remains much less explored. We have previously shown that human epithelial ovarian tumors have increased levels of Cox-1, but not Cox-2. We also observed that Cox-1 is highly expressed in a mouse model of epithelial ovarian cancer (EOC), which lacks p53 but overexpresses c-myc and K-ras or c-myc and Akt. More importantly, a Cox-1-selective inhibitor, SC-560, attenuates EOC growth. In the present investigation, we used various genetically engineered mouse models of EOC to determine whether Cox-1 overexpression is unique to specific genetic and oncogenic alterations or is widespread. These models include: (a) deletion of both p53 and Rb, (b) induction of the transforming region of SV40 under the control of Mullerian inhibitory substance type II receptor, or (c) activation of K-Ras in the absence of Pten locally in the ovarian surface epithelium. We found that these three models, which produce spontaneous EOC, also show up-regulated expression of Cox-1, but not Cox-2. The results provide further evidence that Cox-1 overexpression is common in various models of EOC. Thus, Cox-1 serves as a potential marker of EOC and is a possible target for the prevention and/or treatment of this deadly disease. (Cancer Res 2006; 66(5): 2527-31)

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