Dominant-Stable β-Catenin Expression Causes Cell Fate Alterations and Wnt Signaling Antagonist Expression in a Murine Granulosa Cell Tumor Model

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Abstract
Wnt/β-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/β-catenin signaling occurs in ovarian granulosa cell tumors (GCT) and have created the Catnbflox(ex3)/+;Amhr2cre/+ mouse model, which expresses a dominant-stable mutant of β-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 Catnbflox(ex3)/+;Amhr2cre/+ ovaries bearing pretumoral lesions with control ovaries. Overexpressed genes identified in Catnbflox(ex3)/+;Amhr2cre/+ ovaries included the Wnt/β-catenin signaling antagonists Wif1, Nkd1, Dkk4, and Axin2, consistent with the induction of negative feedback loops that counteract uncontrolled Wnt/β-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 Catnbflox(ex3)/+;Amhr2cre/+ ovaries and GCT but was not associated with increased serum pleiotrophin levels. In situ hybridization analyses using GCT from Catnbflox(ex3)/+;Amhr2cre/+ mice revealed that Wnt/β-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/β-catenin signaling alters the fate of granulosa cells and that the GCT that arise in Catnbflox(ex3)/+;Amhr2cre/+ mice result from the clonal expansion of metaplastic cells. (Cancer Res 2006; 66(4): 1964-73)