A reduction of cyclooxygenase 2 gene dosage counters the ovarian morphological aging and tumor phenotype in Wv mice.
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.
Yang
Wan-Lin
WL
Ovarian Cancer and Tumor Cell Biology Programs, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497, USA.
Cai
Kathy Qi
KQ
Smedberg
Jennifer L
JL
Smith
Elizabeth R
ER
Klein-Szanto
Andres
A
Hamilton
Thomas C
TC
Xu
Xiang-Xi
XX
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D000068579:Celecoxib; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007178:Inbreeding; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin