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From the Department of Pathology,* Weill Medical Collegeof Cornell University, New York; the Departments of MolecularGenetics and CellBiology, Albert Einstein College of Medicine,Bronx; and the Institute of Cancer Genetics,College of Physicians and Surgeons, Columbia University, New York,New York
PTEN mutation and microsatellite instability are
two of the most common genetic alterations in uterine endometrioid
carcinoma. Furthermore, previous studies have suggested an
association between the two alterations, however the basis and
consequence of the association is not understood. Recently it has been
shown that 100% of female Pten+/- mice
develop complex atypical hyperplasia by 32 weeks of age that progresses
to endometrial carcinoma in 
20 to 25% of mice at 40 weeks. In an
attempt to expand this mouse model of endometrial tumorigenesis and to
further our understanding of the association betweenPten mutations and DNA mismatch repair
deficiency, we generated Ptenheterozygous, Mlh1-null (mismatch repair
deficient) mice. Significantly, the majority ofPten+/-/Mlh1-/-mice developed polypoid lesions in the endometrium at 6 to 9 weeks of
age. By 14 to 18 weeks, all of the double-mutant mice had
lesions histologically similar to those seen inPten+/- mice, and two of them
exhibited invasive disease. Moreover, the frequency of loss of
the wild-type Pten allele in the double-mutant mice at
14 to 18 weeks was similar to that seen in lesions from
40-week-old Pten+/- mice. Taken
together, our results indicate that DNA mismatch repair
deficiency can accelerate endometrial tumorigenesis inPten heterozygous mice and suggests that loss of the
wild-type Pten allele is involved in the
development/progression of tumors in this setting.
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