Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/\(\beta\)-Catenin and PTEN

DSpace/Manakin Repository

Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/\(\beta\)-Catenin and PTEN

Show simple item record

dc.contributor.author Tanwar, Pradeep
dc.contributor.author Zhang, LiHua
dc.contributor.author Kaneko-Tarui, Tomoko
dc.contributor.author Curley, Michael D.
dc.contributor.author Taketo, Makoto M.
dc.contributor.author Rani, Poonam
dc.contributor.author Roberts, Drucilla Jane
dc.contributor.author Teixeira, Jose M.
dc.date.accessioned 2011-12-07T00:42:49Z
dc.date.issued 2011
dc.identifier.citation Tanwar, Pradeep S., LiHua Zhang, Tomoko Kaneko-Tarui, Michael D. Curley, Makoto M. Taketo, Poonam Rani, Drucilla J. Roberts, and Jose M. Teixeira. 2011. Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/\(\beta\)-Catenin and PTEN. PLoS ONE 6(6): e20715. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5362746
dc.description.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/\(\beta\)-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 \(\beta\)-catenin that leads to dysregulated nuclear accumulation of \(\beta\)-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated \(\beta\)-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 \(\beta\)-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in \(\beta\)-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/\(\beta\)-catenin and Pten/PI3K signaling. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0020715 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111436/pdf/ en_US
dash.license LAA
dc.subject biology en_US
dc.subject anatomy and physiology en_US
dc.subject reproductive system en_US
dc.subject molecular cell biology en_US
dc.subject signal transduction en_US
dc.subject signaling in cellular processes en_US
dc.subject beta-catenin signaling en_US
dc.subject medicine en_US
dc.subject obstetrics and gynecology en_US
dc.subject gynecologic cancers en_US
dc.subject oncology en_US
dc.subject cancer treatment en_US
dc.subject chemotherapy and drug treatment en_US
dc.title Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/\(\beta\)-Catenin and PTEN en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Teixeira, Jose M.
dc.date.available 2011-12-07T00:42:49Z
dash.affiliation.other HMS^Obstetrics Gynecology and Repro. Bio. - MGH en_US

Files in this item

Files Size Format View
3111436.pdf 9.542Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record

 
 

Search DASH


Advanced Search
 
 

Submitters