Misregulated Wnt/β-Catenin Signaling Leads to Ovarian Granulosa Cell Tumor Development

Abstract

Misregulation of the Wnt/B-catenin signaling pathway is a hallmark of several forms of cancer. Components of the Wnt/ B-catenin pathway are expressed in ovarian granulosa cells; nevertheless, its potential involvement in granulosa cell tumorigenesis has not been examined. To this end, human (n = 6) and equine (n = 18) granulosa cell tumors (GCT) were analyzed for B-catenin expression by immunohistochemistry. Unlike granulosa cells of normal ovaries, most (15 of 24) GCT samples showed nuclear localization of B-catenin, suggesting that activation of the Wnt/B-catenin pathway plays a role in the etiology of GCT. To confirm this hypothesis, Catnb flox(ex3)/+ ; Amhr2 cre/+ mice that express a dominant stable B-catenin mutant in their granulosa cells were generated. These mice developed follicle-like structures containing disorganized, pleiomorphic granulosa by 6 weeks of age. Even in older mice, these follicle-like lesions grew no larger than the size of antral follicles and contained very few proliferating cells. Similar to corpora lutea, the lesions were highly vascularized, although they did not express the luteinization marker Cyp11a1. Catnb flox(ex3)/+ ; Amhr2 cre/+ females were also found to be severely subfertile, and fewer corpora lutea were found to form in response to exogenous gonadotropin compared with control mice. In older mice, the ovarian lesions often evolved into GCT, indicating that they represent a pretumoral intermediate stage. The GCT in Catnb flox(ex3)/+ ; Amhr2 cre/+ mice featured many histopathologic similarities to the human disease, and prevalence of tumor development attained 57% at 7.5 months of age. Together, these studies show a causal link between misregulated Wnt/B-catenin signaling and GCT development and provide a novel model system for the study of GCT biology. (Cancer Res 2005; 65(20): 9206-15)

Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires β-catenin

“…Specifically, ␤-catenin regulates transcription of the central player of estrogen biosynthesis, CYP19A1, via functional interactions with SF1. Prior reports of ␤-catenin-dependent gene expression in the gonad have been interpreted as evidence for the influence of Wnt signaling (30,31,33). We now extend these observations by demonstrating that ␤-catenin is essential for the ability of SF1 to respond to FSH.…”

“…As a mediator of Wnt signaling, ␤-catenin regulates numerous genes involved in development and tumorigenesis (32). Recently, mice that express a constitutively active ␤-catenin mutation only in granulosa cells (GCs) were found to be subfertile and develop GC tumors (33). A role for Wnt signaling and ␤-catenin in embryonic gonad lineage specification has also been suggested (30,31).…”

Secreted frizzled related proteins: Implications in cancers

“…Wnt signalling has been found to be involved in both normal and tumourigenic development of the ovaries [70]; which includes folliculogenesis, luteogenesis, and steroidogenesis, and also tumourigenesis of granulosa cells [71,72]. Wnt ligands are widely expressed in the ovaries [73], are essential for ovarian follicular development and fertility [74], and also contribute to ovarian tumourigenesis through the canonical Wnt signalling pathway [75].…”

Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential

“…Wnt/β-catenin signaling maintains stemness in stem cells from different tissues and prevents them from differentiating [36,70]. For mouse GCs it was demonstrated that WNT2 protein regulates their proliferation through β-catenin pathway [18,81] which when misregulated can lead to ovarian granulosa cell tumor (GCT) [5].…”