TY - JOUR
T1 - Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression
AU - Laguë, Marie Noëlle
AU - Paquet, Marilène
AU - Fan, Heng Yu
AU - Kaartinen, M. Johanna
AU - Chu, Simon
AU - Jamin, Soazik
AU - Behringer, Richard R.
AU - Fuller, Peter J.
AU - Mitchell, Andrew
AU - Doré, Monique
AU - Huneault, Louis M.
AU - Richards, Joanne S.
AU - Boerboom, Derek
N1 - Funding Information:
The Canadian Institutes of Health Research and the Canada Research chair in Ovarian Molecular Biology and Functional Genomics to D.B.; National Institutes of Health (HD16272 and HD07495 to J.S.R. and HD30284 to R.R.B.) and Lalor Foundation Fellowship to S.P.J.
PY - 2008
Y1 - 2008
N2 - The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Ptenflox/flox; Amhr2cre/+). The majority of Ptenflox/flox; Amhr2cre/+ mice featured no ovarian anomalies, but occasionally (∼7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Ptenflox/flox; Amhr2cre/+ GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Ptenflox/flox; Ctnnb1flox(ex3)/+; Amhr2cre/+) resulted in the development of GCT similar to those observed in Ptenflox/flox; Amhr2cre/+ mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT.
AB - The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Ptenflox/flox; Amhr2cre/+). The majority of Ptenflox/flox; Amhr2cre/+ mice featured no ovarian anomalies, but occasionally (∼7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Ptenflox/flox; Amhr2cre/+ GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Ptenflox/flox; Ctnnb1flox(ex3)/+; Amhr2cre/+) resulted in the development of GCT similar to those observed in Ptenflox/flox; Amhr2cre/+ mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT.
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U2 - 10.1093/carcin/bgn186
DO - 10.1093/carcin/bgn186
M3 - Article
C2 - 18687666
AN - SCOPUS:56049110836
SN - 0143-3334
VL - 29
SP - 2062
EP - 2072
JO - Carcinogenesis
JF - Carcinogenesis
IS - 11
ER -