Mouse Model Of Endometrioid Carcinoma

As described previously, several studies have shown that MSI and mutations in PTEN are restricted with rare exceptions, to the estrogen-related endometrioid subtype of endometrial cancer. Furthermore, an association between MSI and PTEN mutations, the most common alterations in endometrioid carcinoma, has been identified, but the nature of the association remains unclear. Taken together, these data support a relationship not only between the two most common genetic alterations in uterine endometri-oid component, but also suggest a fundamental relationship of these alterations with hormonal factors. Understanding these relationships is critical to unraveling the pathogenesis of endometrioid carcinoma. Valuable insights into the molecular genetics and hormonal aspects of endometrial carcinoma have come from the study of primary human tumors and in vitro studies. However, understanding the relationship of genetic alterations and hormones and their biological implications in endometrial tumorigenesis requires an in vivo model system.

Several studies have shown that 100% of female mice lacking one wild-type copy of Pten spontaneously develop a lesion that closely resembles complex atypical hyperplasia in humans. Furthermore, approx 20% of aged (32-40 weeks) mice develop invasive carcinoma with morphological similarities to well-differentiated endometrioid carcinoma (33,34). A recent study has also demonstrated that Pten+/~ mice lacking a functional DNA mismatch repair system (Pten+/~IMlh~'~) have an accelerated onset of hyperplasia and carcinoma (35). An analysis of the neoplastic lesions arising in both Pten+'~ and Pten+l~IMlh~'~ mice show that the lesions (hyperplasias and carcinomas) demonstrate decreased expression of Pten by immunohistochemistry. In addition, in approx 30-60% of the lesions, loss of the wild-type allele of Pten was detected. These findings suggest that loss of Pten function is involved in the progression of endometrial tumorigenesis in this model system. Furthermore, in every lesion detected by light microscopic evaluation, irrespective of size or architecture, P-Akt was detected by immunohistochemical analysis. Although, other downstream targets in the Pten pathway may play a role in the developmentIprogression of endometrial tumorigenesis, these studies indicate a central role for P-Akt.

In the future, this mouse model will be exploited to further our understanding of the pathogenesis of endometrial carcinoma at the molecular level and the interaction of genetic alterations and hormonal influences in this common malignancy of women.

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