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Carcinogenesis Advance Access originally published online on August 6, 2008
Carcinogenesis 2008 29(11):2062-2072; doi:10.1093/carcin/bgn186
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Marie-Noëlle Laguë1, Marilène Paquet2, Heng-Yu Fan3, M. Johanna Kaartinen4, Simon Chu5, Soazik P. Jamin6, Richard R. Behringer6, Peter J. Fuller5, Andrew Mitchell7, Monique Doré8, Louis M. Huneault4, JoAnne S. Richards3 and Derek Boerboom1,3,*

1 Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec J2S 7C6, Canada
2 McGill Cancer Centre and Animal Resources Centre, McGill University, Montréal, Québec H3G 1Y6, Canada
3 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
4 Département des Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec J2S 7C6, Canada
5 Prince Henry's Institute of Medical Research and the Department of Medicine, Monash University, Clayton, Victoria 3168, Australia
6 Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
7 Département de Pathologie, Hôpital Maisonneuve-Rosemont, Montréal, Québec H1T 2M4, Canada
8 Département de Pathologie et Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec J2S 7C6, Canada

* To whom correspondence should be addressed. Tel: +450 773 8521; Fax: +450 778 8103; Email: derek.boerboom{at}umontreal.ca

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.

Abbreviations: FSH, follicle-stimulating hormone; GCT, granulosa cell tumor; GSK3β, glycogen synthase kinase-3β; mTOR, mammalian target of rapamycin; PCR, polymerase chain reaction; PI3K, phosphoinosite-3 kinase

Received April 29, 2008; revised July 24, 2008; accepted August 3, 2008.


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