Expression data from Msh2KO mouse endometrial carcinogenesis

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2(LoxP/LoxP), abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a signature of mitochondrial dysfunction. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: reduced mitochondrial content and structural disruptions in retained mitochondria. Human LS-ECs also exhibited reduced mitochondrial content compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including decreased oxidative phosphorylation and heightened susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS. To achieve Msh2 loss in the endometrium, we bred progesterone receptor Cre knock-in (PR-Cre) mice to Msh2(LoxP/LoxP) mice to produce PR-Cre+Msh2(LoxP/LoxP) mice with targeted loss of MSH2 expression in tissues that express PR, including the uterus (hereafter abbreviated Msh2KO). Control mice contain Msh2(LoxP/LoxP) without PR-Cre. We profiled Msh2KO endometrial tumors, Msh2KO benign endometrium, and control mouse benign endometrium using transcriptomic profiling of microdissected glands via microarray analysis (ClariomD, Affymetrix). We compared expression profiles from Msh2KO tumors (N=7), Msh2KO mice with benign endometrium (N=6), and age-matched control mice (N=4). All mice were 12-16 months of age at time of sacrifice and tissue harvest.