Dominant-stable beta-catenin expression causes cell fate alterations and Wnt signaling antagonist expression in a murine granulosa cell tumor model.
Wnt/beta-catenin signaling is normally involved in embryonic development and tissue homeostasis, and its misregulation leads to several forms of cancer. We have reported that misregulated Wnt/beta-catenin signaling occurs in ovarian granulosa cell tumors (GCT) and have created the Catnb(flox(ex3)/+);Amhr2(cre/+) mouse model, which expresses a dominant-stable mutant of beta-catenin in granulosa cells and develops late-onset GCT. To study the mechanisms leading to GCT development, gene expression analysis was done using microarrays comparing Catnb(flox(ex3)/+);Amhr2(cre/+) ovaries bearing pretumoral lesions with control ovaries. Overexpressed genes identified in Catnb(flox(ex3)/+);Amhr2(cre/+) ovaries included the Wnt/beta-catenin signaling antagonists Wif1, Nkd1, Dkk4, and Axin2, consistent with the induction of negative feedback loops that counteract uncontrolled Wnt/beta-catenin signaling. Expression of the antagonists was localized to cells forming the pretumoral lesions but not to normal granulosa cells. Microarray analyses also revealed the ectopic expression of bone markers, including Ibsp, Cdkn1c, Bmp4, and Tnfrsf11b, as well as neuronal/neurosecretory cell markers, such as Cck, Amph, Pitx1, and Sp5. Increased expression of the gene encoding the cytokine pleiotrophin was also found in Catnb(flox(ex3)/+);Amhr2(cre/+) ovaries and GCT but was not associated with increased serum pleiotrophin levels. In situ hybridization analyses using GCT from Catnb(flox(ex3)/+);Amhr2(cre/+) mice revealed that Wnt/beta-catenin antagonists and neuronal markers localized to a particular cell population, whereas the bone markers localized to a distinct cell type associated with areas of osseous metaplasia. Together, these results suggest that misregulated Wnt/beta-catenin signaling alters the fate of granulosa cells and that the GCT that arise in Catnb(flox(ex3)/+);Amhr2(cre/+) mice result from the clonal expansion of metaplastic cells.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Derek
D
Boerboom
Lisa D
LD
White
Sophie
S
Dalle
José
J
Courty
Joanne S
JS
Richards
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D060466:Axin Protein; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005260:Female; D015870:Gene Expression; D006106:Granulosa Cell Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000502:physiology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000096:biosynthesis*
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C111729:Axin2 protein, mouse; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C424446:Nkd1 protein, mouse; D012097:Repressor Proteins; C118544:Wif1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; C066845:pleiotrophin