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Home / Equine Research Bank / Cancer Res / Misregulated Wnt/beta-catenin signaling leads to ovarian gra...
Cancer research2005; 65(20); 9206-9215; doi: 10.1158/0008-5472.CAN-05-1024

Misregulated Wnt/beta-catenin signaling leads to ovarian granulosa cell tumor development.

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.
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Publication Date: 2005-10-19 PubMed ID: 16230381DOI: 10.1158/0008-5472.CAN-05-1024Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article demonstrates a link between improper regulation of the Wnt/beta-catenin signaling pathway and the development of ovarian granulosa cell tumors.

Study Background

  • The Wnt/beta-catenin signaling pathway plays a crucial role in cell growth and division (proliferation), renewal and survival. Its misregulation often induces various types of cancer. Even though components of the pathway are expressed in ovarian granulosa cells, previous research had not explored its involvement in granulosa cell tumorigenesis.

Objective and Methodology

  • The researchers sought to understand the pathway’s potential role in the development of granulosa cell tumors (GCT), by analyzing the beta-catenin expression of human (6 samples) and equine (18 samples) GCTs through immunohistochemistry.

Results

  • Unlike normal granulosa cells, majority of the GCT samples exhibited nuclear localization of beta-catenin, implying that activation of the Wnt/beta-catenin pathway might influence GCT development.
  • To verify this, researchers generated mice strain, Catnb(flox(ex3)/+); Amhr2(cre/+), with a stably expressed dominant beta-catenin mutant in their granulosa cells. The mice developed follicle-like structures containing disorganized granulosa by six weeks of age.
  • These mutations led to abnormalities such as severely reduced fertility, fewer corpora lutea formed in response to exogenous gonadotropin, disorganized granulosa cells, and eventually granulosa cell tumors.
  • The tumors developed in the experimental mice displayed many histopathologic similarities to human GCT, confirming a potential relevance to human ovarian health.

Conclusion

  • The study concluded that misregulated Wnt/beta-catenin signaling contributes significantly to GCT development. It also provided a new model for studying GCT biology, thereby offering potential for further research and treatment strategies.

Cite This Article

APA
Boerboom D, Paquet M, Hsieh M, Liu J, Jamin SP, Behringer RR, Sirois J, Taketo MM, Richards JS. (2005). Misregulated Wnt/beta-catenin signaling leads to ovarian granulosa cell tumor development. Cancer Res, 65(20), 9206-9215. https://doi.org/10.1158/0008-5472.CAN-05-1024

Publication

Cancer research
ISSN: 0008-5472
NlmUniqueID: 2984705R
Country: United States
Language: English
Volume: 65
Issue: 20
Pages: 9206-9215

Researcher Affiliations

Boerboom, Derek
  • Department of Molecular and Cellular Biology and Center for Comparative Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Paquet, Marilene
    Hsieh, Minnie
      Liu, Jinsong
        Jamin, Soazik P
          Behringer, Richard R
            Sirois, Jean
              Taketo, Makoto M
                Richards, Joanne S

                  MeSH Terms

                  • Animals
                  • Disease Models, Animal
                  • Female
                  • Granulosa Cell Tumor / genetics
                  • Granulosa Cell Tumor / metabolism
                  • Granulosa Cell Tumor / pathology
                  • Horses
                  • Humans
                  • Immunohistochemistry
                  • Mice
                  • Mice, Transgenic
                  • Ovarian Neoplasms / genetics
                  • Ovarian Neoplasms / metabolism
                  • Ovarian Neoplasms / pathology
                  • Receptors, Peptide / genetics
                  • Receptors, Transforming Growth Factor beta
                  • Signal Transduction
                  • Wnt Proteins / biosynthesis
                  • Wnt Proteins / genetics
                  • beta Catenin / biosynthesis
                  • beta Catenin / genetics

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