Skip Navigation



Carcinogenesis Advance Access published online on February 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp051
This Article
Right arrow Advance Access manuscript (PDF)
Right arrow All Versions of this Article:
30/5/869    most recent
bgp051v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Boyer, A.
Right arrow Articles by Boerboom, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Boyer, A.
Right arrow Articles by Boerboom, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dysregulation of WNT/CTNNB1 and PI3K/AKT signaling in testicular stromal cells causes granulosa cell tumor of the testis

Alexandre Boyer2, Marilène Paquet3, Marie-Noëlle Laguë1, Louis Hermo4 and Derek Boerboom1,2,*

1 Centre de Recherche en Reproduction Animale, Université de Montréal, St-Hyacinthe, Québec J2S 7C6, Canada
2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
3 Comparative Medicine & Animal Resources Centre
4 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada

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

Synergistic effects of dysregulation of the WNT/CTNNB1 and PI3K/AKT pathways are thought to be important for the development and progression of many forms of cancer, including the granulosa cell tumor of the ovary. Sustained WNT/CTNNB1 signaling in Sertoli cells causes testicular degeneration and the formation of foci of poorly differentiated stromal cells in the seminiferous tubules in mice. To test if concomitant dysregulation of the WNT/CTNNB1 and PI3K/AKT pathways could synergize to cause testicular cancer, Ptentm1Hwu/tm1Hwu;Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ mice that express a dominant stable CTNNB1 mutant and lack the expression of PTEN in their Sertoli cells were generated. These mice developed aggressive testicular cancer with 100% penetrance by five weeks of age, and 44% of animals developed pulmonary metastases by 4 months, whereas Ptentm1Hwu/tm1Hwu;Amhr2tm3(cre)Bhr/+controls were phenotypically normal. Surprisingly, the tumors could not be classified as Sertoli cell tumors, but rather bore histologic and ultrastructural characteristics of granulosa cell tumors of the testis (GCTT). Ptentm1Hwu/tm1Hwu;Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ testicular tumors did not express CYP17, CYP19, GCNA, ESR1 or PGR, but expressed the early granulosa cell markers WNT4 and FOXL2, confirming the diagnosis of GCTT. Immunohistochemical analyses of Ptentm1Hwu/tm1Hwu;Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ GCTT demonstrated a tumor marker profile similar to that reported in human GCTT. Immunoblotting analyses revealed high levels of phosphorylation of AKT and the PI3K/AKT signaling effector FOXO1A in Ptentm1Hwu/tm1Hwu;Ctnnb1tm1Mmt/+;Amhr2tm3(cre)Bhr/+ GCTT, suggesting the involvement of FOXO1A in the mechanism of GCTT development. Together, these data provide the first insights into the molecular etiology of GCTT and the first animal model for the study of GCTT biology.

Received December 18, 2008; revised February 4, 2009; accepted February 14, 2009.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.