A Reduction of Cyclooxygenase 2 Gene Dosage Counters the Ovarian Morphological Aging and Tumor Phenotype in Wv Mice

• Published in: The American journal of pathology Vol. 170; no. 4; pp. 1325 - 1336
• Main Authors: Yang, Wan-Lin, Cai, Kathy Qi, Smedberg, Jennifer L, Smith, Elizabeth R, Klein-Szanto, Andres, Hamilton, Thomas C, Xu, Xiang-Xi
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2007; ASIP; American Society for Investigative Pathology
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Aging - pathology; Animals; Biological and medical sciences; Blotting, Western; Celecoxib; Cell Transformation, Neoplastic - drug effects; Cyclooxygenase 2 - deficiency; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Epithelium - metabolism; Epithelium - pathology; Female; Female genital diseases; Gene Dosage; Gynecology. Andrology. Obstetrics; Heterozygote; Homozygote; Humans; Inbreeding; Indomethacin - administration & dosage; Indomethacin - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - drug effects; Ovary - metabolism; Ovary - pathology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Regular; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Tumors; Gene dosage; Enzyme; Cyclooxygenase 2; Ageing; Rodentia; Female genital diseases; Ovarian diseases; Vertebrata; Anatomic pathology; Phenotype; Reduction; Mammalia; Mouse; Animal; Morphology; Oxidoreductases; Age; Ovarian tumor
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.060769

Menopausal ovaries undergo morphological changes, known as ovarian aging, which are implicated in the high incidence of ovarian cancer occurring during the perimenopausal and immediate postmenopausal periods. The germ cell-deficient Wv mice recapitulate these postmenopausal alterations in ovarian morphology and develop tubular adenomas. We demonstrate that a reduction of cyclooxygenase 2 gene dosage rescued the ovarian aging phenotype of the Wv mice, whereas homozygous deletion was accompanied by a compensatory increase in ovarian cyclooxygenase 1 expression and prostaglandin E2 synthesis. Cyclooxygenase inhibitors also reduced the tumor phenotype in a preliminary study. These findings suggest that increased cyclooxygenase activity contributes to the preneoplastic morphological changes of the ovarian surface epithelium, which can be reversed by a reduction of gene dosage achieved by either genetic or pharmacological approaches.