Details

Autor(en) / Beteiligte

• Laguë, Marie-Noëlle
• Paquet, Marilène
• Fan, Heng-Yu
• Kaartinen, M. Johanna
• Chu, Simon
• Jamin, Soazik P.
• Behringer, Richard R.
• Fuller, Peter J.
• Mitchell, Andrew
• Doré, Monique
• Huneault, Louis M.
• Richards, JoAnne S.
• Boerboom, Derek

Titel

Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression

Ist Teil von

• Carcinogenesis (New York), 2008-11, Vol.29 (11), p.2062-2072

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2008

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.