RGD Reference Report - Dominant-stable beta-catenin expression causes cell fate alterations and Wnt signaling antagonist expression in a murine granulosa cell tumor model. - Rat Genome Database

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Dominant-stable beta-catenin expression causes cell fate alterations and Wnt signaling antagonist expression in a murine granulosa cell tumor model.

Authors: Boerboom, D  White, LD  Dalle, S  Courty, J  Richards, JS 
Citation: Boerboom D, etal., Cancer Res. 2006 Feb 15;66(4):1964-73.
RGD ID: 1643593
Pubmed: PMID:16488995   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-05-3493   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
granulosa cell tumor  ISOBmp4 (Mus musculus)1643593; 1643593mRNA:increased expression:ovaryRGD 
granulosa cell tumor  IEP 1643593; 1643593mRNA:increased expression:ovaryRGD 
granulosa cell tumor  ISOCtnnb1 (Mus musculus)1643593; 1643593 RGD 
granulosa cell tumor  IAGP 1643593 RGD 
granulosa cell tumor  ISOWif1 (Mus musculus)1643593; 1643593mRNA:increased expression:ovaryRGD 
Metaplasia  ISOAxin2 (Mus musculus)1643593; 1643593associated with Granulosa Cell Tumor and mRNA:increased expression:ovaryRGD 
Metaplasia  IEP 1643593associated with Granulosa Cell Tumor and mRNA:increased expression:ovaryRGD 

Objects Annotated

Genes (Rattus norvegicus)
Axin2  (axin 2)
Bmp4  (bone morphogenetic protein 4)
Ctnnb1  (catenin beta 1)
Wif1  (Wnt inhibitory factor 1)

Genes (Mus musculus)
Axin2  (axin 2)
Bmp4  (bone morphogenetic protein 4)
Ctnnb1  (catenin beta 1)
Wif1  (Wnt inhibitory factor 1)

Genes (Homo sapiens)
AXIN2  (axin 2)
BMP4  (bone morphogenetic protein 4)
CTNNB1  (catenin beta 1)
WIF1  (WNT inhibitory factor 1)

Objects referenced in this article
Gene ATP7B ATPase copper transporting beta Homo sapiens
Gene Atp7b ATPase, Cu++ transporting, beta polypeptide Mus musculus
Gene Atp7b ATPase copper transporting beta Rattus norvegicus

Additional Information