Roles of Deletion of Arid1a, a Tumor Suppressor, in Mouse Ovarian Tumorigenesis

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Abstract

The chromatin remodeling gene,ARID1A, has been implied as a tumor suppressor, and its somatic inactivating mutations occur in a wide variety of human cancers, most frequently in ovarian and uterine endometrioid and ovarian clear cell carcinomas. Tumors withARID1Amutations also frequently harborPTENorPIK3CAmutations, suggesting their collaboration in tumorigenesis. Here, we used a conditional knockout mouse model in whichArid1aandPtenwere deleted either individually or in combination in the mouse ovarian surface epithelium. After 6 months, 59.1% of mice withArid1aandPtendouble knockout developed ovarian endometrioid or undifferentiated carcinoma, whereas the remaining mice showed hyperplasia of ovarian surface epithelium. In contrast, 52 mice with homozygous or heterozygous deletion in eitherArid1aorPtendid not develop ovarian lesions. These results demonstrate that inactivation ofArid1aalone is insufficient for tumor initiation but it requires additional genetic alteration(s) such asPtendeletion to drive tumorigenesis.

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