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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 consequences of the association of DNA mismatch repair (MMR) deficiency and PTEN mutations have not been thoroughly studied. In an attempt to address these issues, we have exploited a mouse model of endometrial tumorigenesis. We have analyzed 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 (C57BL6/129SvJ 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 in both backgrounds (0% C57BL6/129SvJ, 5.89% CD-1) while the frequency of LOH of Pten in Pten+/−/Mlh1-/- (54.8%) is similar to that in C57BL6/129SvJ (56.8%) and CD-1 Pten+/− mice (57.5%). Thus, biallelic inactivation of Pten (LOH or intragenic mutation) was present in 71%, 56.8% and 60% of Pten+/−/Mlh1-/-, C57BL6/129SvJ and CD-1 Pten+/− mice, respectively. However, no mutations were found at coding region repeats of other genes known to play a role in endometrial carcinoma. Taken together, these findings indicate specific mutations in Pten are a consequence of MMR deficiency in this setting. As noted above, we also generated congenic C57BL6 Pten+/− mice as well as a N10 generation in the outbred CD-1 strain, a strain used for estrogen induced endometrial cancer 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 the F1 hybrids. 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 Ptenmutations in the development of endometrial carcinoma.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]