Introduction: Endometrial cancer (EC) is the 4th most common cancer in US women. The relentless rise of EC frequency and mortality is due in part to the obesity epidemic (Annual Report to the Nation on the Status of Cancer, 2019). Obesity is associated with higher risk of both developing and dying from EC. The microbiome is known to play a complex role in the regulation of obesity and cancer, yet the inter-relationship of obesity, the uterine tumor microbiota, and EC pathogenesis is unknown, including the potential influence of menopausal status. Thus, we characterized the microbiota of the malignant uterus using pre- and postmenopausal, obese and lean genetically engineered mouse models of endometrioid EC.

Methods: The Lkb1fl/flp53fl/fl mouse is a genetically engineered, preclinical model of endometrioid EC. At 3 wks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet (LFD, 10% calories from fat) versus a high-fat diet (HFD, 60% calories from fat) to mimic diet-induced obesity. At 6 wks of age, the right uterine horn was injected with AdenoCre virus to delete Lkb1 and p53 and induce EC. Concurrently, mice either underwent bilateral oophorectomy to induce the postmenopausal state or retained their ovaries to maintain a premenopausal status. EC tumors were collected from all mice 12 wks after tumor induction. The microbiota profiles were characterized by bacterial 16S rRNA high-throughput sequencing, and the data were analyzed using Qiime2 and MicrobiomeAnalyst.

Results: When analyzed by obesity and menopausal status, we observed significant differences in the EC microbiota composition of Lkb1fl/flp53fl/fl mice at the phylum and genus level. OD1 and TM7 phyla abundance was higher among obese post- versus premenopausal mice (p<0.05). At the genus level, there was a significant increase in the abundance of Delftia (p<0.01) in obese premenopausal mice whereas the abundance of Helicobacter (p=0.01), Oscillospira (p<0.01), and Ruminococcus (p<0.01) was increased in obese postmenopausal mice. In lean mice, the phylum-level abundance of Proteobacteria (p<0.01) was increased in pre- versus postmenopausal mice. There was also a higher abundance of Delftia (p<0.01) in lean pre- versus postmenopausal mice at the genus level. In postmenopausal mice, the relative abundance of Helicobacter (p=0.02) was increased in obese versus lean mice.

Conclusion: There were distinct differences in the bacterial composition of the ECs in Lkb1fl/flp53fl/fl mice according to obesity and menopausal status, suggesting that the microbiome may play a role in the pathogenesis of obesity-driven EC.

Citation Format: Gabrielle M. Hawkins, Amber N. McCoy, Wenchuan Sun, Temitope Keku, Chunxiao Zhou, Wendy R. Brewster, Victoria L. Bae-Jump. Impact of obesity on the uterine microbiome in pre- and postmenopausal mice with endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B29.