DNA mismatch repair deficiency accelerates endometrial tumorigenesis in Pten heterozygous mice

Hong Wang, Wayne Douglas, Marie Lia, Winfried Edelmann, Raju Kucherlapati, Katrina Podsypanina, Ramon Parsons, Lora Hedrick Ellenson

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55 Scopus citations

Abstract

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 between Pten mutations and DNA mismatch repair deficiency, we generated Pten heterozygous, Mlh1-null (mismatch repair deficient) mice. Significantly, the majority of Pten+/-/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 in Pten+/- 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 in Pten heterozygous mice and suggests that loss of the wild-type Pten allele is involved in the development/progression of tumors in this setting.

Original languageEnglish (US)
Pages (from-to)1481-1486
Number of pages6
JournalAmerican Journal of Pathology
Volume160
Issue number4
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Wang, H., Douglas, W., Lia, M., Edelmann, W., Kucherlapati, R., Podsypanina, K., Parsons, R., & Ellenson, L. H. (2002). DNA mismatch repair deficiency accelerates endometrial tumorigenesis in Pten heterozygous mice. American Journal of Pathology, 160(4), 1481-1486. https://doi.org/10.1016/S0002-9440(10)62573-4