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Abstract Obesity is a rising epidemic in the United States, with approximately 50% of adult women predicted to be obese by 2030. Obesity is a risk factor for endometrial hyperplasia (EH), which is characterized by the benign overgrowth of the endometrial epithelium and is considered a precursor lesion for endometrial cancer (EC). Somatic PTEN mutations are commonly observed in EH and EC, with PTEN loss being one of the earliest mutations observed in the progression to EC. Previous obesity work in our lab utilized high-fat diet (HFD) -induced obese WT mice and found that obesity affected different cell types within the endometrium, including non-tumor prone cells. Our preliminary findings suggest that 60% HFD prolongs the estrus stage of the estrus cycle in WT mice. The aims of this study are to determine the cell-specific effects of obesity on the endometrial epithelia carrying PTEN mutations. Female PTENfl/fl; Pax8Cre/+ mutant and Pax8Cre+/+ control mice on a C57BL/6J background were fed either a 60% HFD or it’s sucrose-matched control diet (CD) for a minimum of 22 weeks. Weekly mouse and food weights were collected. Mice were tested for glucose tolerance after being on diet for at least 4. 5 months. Uterus and blood were collected at estrus stage. Uteri were processed for single-cell RNA seq. PTENfl/fl; Pax8Cre/+ mice on both the HFD and CD had a diminished weight gain compared to Pax8Cre+/+ mice on the same diet. HFD-treated mice exhibited hyperphagia, weighed significantly more than the CD mice, and demonstrated glucose intolerance. H Pax8Cre/+ uteri confirmed epithelial-specific loss of PTEN and displayed endometrial hyperplasia. PTENfl/fl; Pax8Cre/+ uteri had an influx of Ly6G+ neutrophils invading the endometrial epithelium compared to the Pax8Cre+/+ mice. Strikingly in PTENfl/+; Pax8Cre/+ we observe clonal loss of PTEN immunoreactivity in a subset of endometrial glands with similar phenotypic features. We propose that obesity’s impact on non-tumor cell types within the endometrium will be shaped by early genetic mutations in tumor-prone epithelia. Citation Format: Hilary J. Skalski, Shannon K. Harkins, Amelia R. Arendt, Madison MacLachlan, Katelyn Becker, Marc Wegener, Marie Adams, Galen Hostetter, Ronald L. Chandler. Addressing obesity’s impact on the PTEN mutant endometrium abstract. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (5Suppl): Abstract nr A009.
Skalski et al. (Fri,) studied this question.