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Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN.

Tanwar PS, Zhang L, Kaneko-Tarui T, Curley MD, Taketo MM, Rani P, Roberts DJ, Teixeira JM - PLoS ONE (2011)

Bottom Line: 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.These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling.

View Article: PubMed Central - PubMed

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.

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.

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Elevated levels of active mTOR in mouse ovarian tumors and in human OEAs.Sections from ovaries of control (A, D, & G) and mutant mice (B, C, E, F, H, & I) were analyzed by IHC for mTOR, pmTOR, and pS6K, as indicated. IHC of mTOR (J & N) , pmTOR (K & O), S6K (L & P) and pS6K (M & Q) in normal postmenopausal ovaries (n = 3) and in human OEAs (n = 4) as indicated. Bars = 50 um.
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pone-0020715-g004: Elevated levels of active mTOR in mouse ovarian tumors and in human OEAs.Sections from ovaries of control (A, D, & G) and mutant mice (B, C, E, F, H, & I) were analyzed by IHC for mTOR, pmTOR, and pS6K, as indicated. IHC of mTOR (J & N) , pmTOR (K & O), S6K (L & P) and pS6K (M & Q) in normal postmenopausal ovaries (n = 3) and in human OEAs (n = 4) as indicated. Bars = 50 um.

Mentions: Mammalian target of rapamycin (mTOR) signaling is a master regulator of cellular proliferation and is an attractive therapeutic target for a variety of cancers [37]. Dysregulated Wnt/β-catenin signaling has been shown to induce mTOR expression and signaling in intestinal polyps [38] of mutant APC mice, and we have shown that mTOR expression is elevated in uteri of Amhr2-Cre;Ctnnb1Δ(ex3)/+ mice [19]. In Fig. 3X, we observed elevated expression by western analysis of pS6K, a downstream target of mTOR kinase activity, in the Amhr2-Cre;Ctnnb1Δ(ex3)/+ and Amhr2-Cre;Ctnnb1Δ(ex3)/+;PtenΔ/Δ tumors compared to control mice. Immunohistochemistry of mTOR, p mTOR, and pS6K expression was performed to confirm that the increased expression was isolated to the tumor cells in mutant ovaries (Fig. 4A–I). We also observed strong expression for mTOR, p mTOR, and pS6K in human OEAs (4/4) (Fig. 4J–Q), which in Fig. 1, we showed also had induced levels of nuclear β-catenin.


Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/β-catenin and PTEN.

Tanwar PS, Zhang L, Kaneko-Tarui T, Curley MD, Taketo MM, Rani P, Roberts DJ, Teixeira JM - PLoS ONE (2011)

Elevated levels of active mTOR in mouse ovarian tumors and in human OEAs.Sections from ovaries of control (A, D, & G) and mutant mice (B, C, E, F, H, & I) were analyzed by IHC for mTOR, pmTOR, and pS6K, as indicated. IHC of mTOR (J & N) , pmTOR (K & O), S6K (L & P) and pS6K (M & Q) in normal postmenopausal ovaries (n = 3) and in human OEAs (n = 4) as indicated. Bars = 50 um.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111436&req=5

pone-0020715-g004: Elevated levels of active mTOR in mouse ovarian tumors and in human OEAs.Sections from ovaries of control (A, D, & G) and mutant mice (B, C, E, F, H, & I) were analyzed by IHC for mTOR, pmTOR, and pS6K, as indicated. IHC of mTOR (J & N) , pmTOR (K & O), S6K (L & P) and pS6K (M & Q) in normal postmenopausal ovaries (n = 3) and in human OEAs (n = 4) as indicated. Bars = 50 um.
Mentions: Mammalian target of rapamycin (mTOR) signaling is a master regulator of cellular proliferation and is an attractive therapeutic target for a variety of cancers [37]. Dysregulated Wnt/β-catenin signaling has been shown to induce mTOR expression and signaling in intestinal polyps [38] of mutant APC mice, and we have shown that mTOR expression is elevated in uteri of Amhr2-Cre;Ctnnb1Δ(ex3)/+ mice [19]. In Fig. 3X, we observed elevated expression by western analysis of pS6K, a downstream target of mTOR kinase activity, in the Amhr2-Cre;Ctnnb1Δ(ex3)/+ and Amhr2-Cre;Ctnnb1Δ(ex3)/+;PtenΔ/Δ tumors compared to control mice. Immunohistochemistry of mTOR, p mTOR, and pS6K expression was performed to confirm that the increased expression was isolated to the tumor cells in mutant ovaries (Fig. 4A–I). We also observed strong expression for mTOR, p mTOR, and pS6K in human OEAs (4/4) (Fig. 4J–Q), which in Fig. 1, we showed also had induced levels of nuclear β-catenin.

Bottom Line: 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.These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/β-catenin and Pten/PI3K signaling.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus