27 - 30 May 2005

GENETIC MOUSE MODEL OF ENDOMETRIAL CARCINOMA H. Wang, W. Douglas and L. Ellenson Weill Medical College of Cornell University New York, NY 10021 USA

The importance of the PTEN tumor suppressor gene in the development of endometrial carcinoma is indisputable. However, the mechanisms by which mutations in this gene contribute to endometrial tumorigenesis remain incompletely elucidated. In light of numerous previous studies, inactivation of PTEN appears to be a relatively early event in the pathogenesis of endometrial carcinoma.

However, the role of PTEN in the development of hyperplasia and its progression to invasive disease is not well understood. Furthermore, the relationship of DNA mismatch repair (MMR) deficiency and PTEN mutations, while reproducible, remains unknown. In an attempt to address these issues, we have exploited a mouse model of endometrial tumorigenesis.

We have analysed the status of the remaining wild-type Pten allele, and mutations in other genes known to play a role in endometrial carcinoma, in Pten heterozygous mice (C57BL6/129Sv and CD-1 strains) and Pten+/-/Mlh1-/- double mutants. The majority of complex atypical hyperplasias (CAHs) showed biallelic inactivation of Pten mediated through LOH or intragenic mutation of the wild-type allele in both Pten+/-/Mlh1-/- and Pten+/- mice. This result, together with the low incidence of invasive disease (5 of 40) in these mice, suggests that complete loss of Pten alone is not sufficient for the development of invasive endometrial carcinoma. Interestingly, a higher frequency (35.7%) of Pten mutations at coding repeat sequences was present in Pten+/-/Mlh1-/- mice compared with Pten+/- mice (0%, 5.89% in C57BL6/129Sv and CD-1 strains, respectively). This finding indicates specific mutations in Pten are a consequence of MMR deficiency in this setting.

Previous studies have shown significant differences in the development of estrogen-induced endometrial carcinoma between different strains of mice, and the CD-1 strain develops estrogen-induced endometrial cancer with a high frequency. To address the influence of genetic background on the development of endometrial carcinoma in Pten+/- mice, we generated congenic C57BL6 Pten+/- mice as well as a N10 generation in the outbred CD-1 strain, a strain often used for the estrogen induced models.

We found that the N10 generation of C57BL6 Pten+/- mice completely lost the endometrial phenotype, while the CD-1 Pten+/- mice developed CAHs similar to the C57BL6/129SvJ mixed strain, both qualitatively and quantitatively. Notably, when the N10 C57BL6 is backcrossed to 129SvJ strain, the endometrial phenotype was restored in F1 hybrid. These results suggest that the development of endometrial lesions in Pten+/- mice is strain dependent and that CD-1 Pten+/- mice may be useful for investigating the relationship of hormones and Pten mutations in the development of endometrial carcinoma.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract