Abstract
Misregulation of the Wnt/beta-catenin signaling pathway is a hallmark of several forms of cancer. Components of the Wnt/beta-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 beta-catenin expression by immunohistochemistry. Unlike granulosa cells of normal ovaries, most (15 of 24) GCT samples showed nuclear localization of beta-catenin, suggesting that activation of the Wnt/beta-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 beta-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/beta-catenin signaling and GCT development and provide a novel model system for the study of GCT biology.
Highlights
Ovarian cancer is currently the fifth leading cause of cancer deaths in North American women [1]
In the case of tumors that arise from the ovarian surface epithelium, this can be attributed in part to our poor understanding of the biology of this particular cell type, leading to difficulties in targeting mutations to www.aacrjournals.org epithelial cells [43]
For granulosa cell tumor (GCT), the problem has been further compounded by a dearth of information regarding the genetic lesions involved in GCT development [5]
Summary
Ovarian cancer is currently the fifth leading cause of cancer deaths in North American women [1]. Unlike many other forms of cancer, age-adjusted incidence and death rates from ovarian cancer have improved very little over the past z30 years [1]. Most research in this field has focused narrowly on neoplasms that arise from the ovarian surface epithelium, as these comprise the majority of. Contrary to what is seen in humans, tumors of the ovarian surface epithelium are relatively uncommon in most domestic species In species such as the cow, ewe, and mare, GCT is by far the most frequently observed neoplastic disease of the ovary [4]
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