title: Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN.
abstract: Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/β-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in β-catenin that leads to dysregulated nuclear accumulation of β-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated β-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear β-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in β-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Tanwar
authors.forename: LiHua
authors.initials: L
authors.lastname: Zhang
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kaneko-Tarui
authors.forename: Michael D
authors.initials: MD
authors.lastname: Curley
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Poonam
authors.initials: P
authors.lastname: Rani
authors.forename: Drucilla J
authors.initials: DJ
authors.lastname: Roberts
authors.forename: Jose M
authors.initials: JM
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D018269:Carcinoma, Endometrioid / Q000201:enzymology* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus