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

Abstract

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 E 2 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. (Am J

Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and utility of TMPRSS4 as a combinatorial molecular target

“…Indeed, a strategy that blocks production of PGE 2 or EP receptor-mediated signaling showed a reduction in cancer cell growth in vitro and in vivo (19)(20)(21). Heterozygous deletion of the COX-2 gene also reduced growth of ovarian cancer (22). These reports suggest that cellular signaling via the PGE 2 -EP receptor can be a target for therapy of ovarian cancer and its metastasis.…”

Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis

“…The Wv mouse (C57BL/6J-KitW-v) breeding pairs were originally obtained from Jackson Laboratory in 2002 and were maintained by inbreeding, as well as occasionally backcrossed with C57BL/6J mice in our mouse facility for the last 10 years. Several studies using the mice have been reported (34,41,46). The compound-mutant inbreeding colonies were established by crossing Wv/ϩ mice with p27 ϩ/Ϫ , p53 ϩ/Ϫ , or p53 fl/fl (p53 allele/gene is flanked by loxP sites) mice.…”

“…An immunohistochemistry procedure was performed to analyze paraffin-embedded tissues according to the standard procedure (41,45). Antigen retrieval was performed by boiling the slides submerged in antigen retrieval buffer (Dako) for 20 min.…”

“…At around 8 weeks of age, when wild-type littermates reach reproductive maturity, the Wv/Wv ovaries are depleted of follicles, and subsequently, ovarian tubular adenomas initiate (40,41). These epithelial tumor cells are derived from the ovarian surface, and the majority of the lesions either exhibit inclusion cyst-like structures or resemble the surface deep invaginations/papillomatosis that is commonly observed in postmenopausal human ovaries (41,(42)(43)(44). Although dysplastic morphology is evident in some epithelial compartments of the tubular adenomas, the ovarian epithelial tubular structures in Wv mice are considered benign tumors, and the lesions are confined to ovarian tissues and do not become metastatic.…”

“…Wv female mice have a greatly decreased number of ovarian follicles due to a mutation in c-Kit that greatly reduces tyrosine kinase activity (36)(37)(38)(39). At around 8 weeks of age, when wild-type littermates reach reproductive maturity, the Wv/Wv ovaries are depleted of follicles, and subsequently, ovarian tubular adenomas initiate (40,41). These epithelial tumor cells are derived from the ovarian surface, and the majority of the lesions either exhibit inclusion cyst-like structures or resemble the surface deep invaginations/papillomatosis that is commonly observed in postmenopausal human ovaries (41,(42)(43)(44).…”