Abstract 3393: Deciphering colorectal cancer: A model to study sex-based differences and role of estrogen amidst obesity

Abstract

Abstract Worldwide statistics indicate that obesity is increasing globally, mostly due to the consumption of Western diet. The literature points out that obesity is a potent risk factor for the development of colorectal cancer (CRC). Interestingly, CRC incidence is higher in men compared to women, and the sex hormone estrogen protects reproductive-age females from CRC despite obesity. In this project, we aim to understand the sex-based differences and protective role of estrogen in obesity-influenced CRC. An improved mouse model was devised where the effects of obesity and estrogen in CRC could be meticulously studied. We deployed 4-5-week-old male and female FVB/NJ mice and performed either sham surgery (males and females) or bilateral ovariectomy (OVX) (females). Post one week of recovery, all mice were randomly sub-grouped into either low-fat diet (LFD, 10% fat) or high-fat diet (HFD, 60% fat) groups, weekly injected with a colon-specific carcinogen azoxymethane (AOM; 5 mg/kg for week 1, 10 mg/kg for weeks 2-6), and cyclically every 4-5 days injected 17-beta-estradiol (E2; 4 μg/mouse) to a group of OVX mice for the study period of 22 weeks. The body weight of all mice was tracked every week. A whole-body composition analysis after 22 weeks showed that males and OVX females are more obese compared to females with sham surgery and OVX females with E2 injection (OVX+E2), respectively. Additionally, mice on HFD had a higher body weight compared to those on LFD; however, the absence of estrogen in OVX females led them to have higher body weight compared to sham and OVX+E2 females. Moreover, a significant difference was observed in the tumor size between males and females, females and OVX females, and OVX and OVX+E2 females. Study models have rarely incorporated both sex-dependent differences and diet-induced obesity in understanding CRC. With the current study model, it is anticipated to learn more about these differences at molecular, cellular, and metabolic levels. Acknowledgments: 1) NIH/NCI R15 [To HS, XW]; 2) Miami University CFR Faculty Research Grants [To HS, XW, JZ]; 3) Miami University's College of Education, Health, and Society Interdisciplinary Research Seed Grant [To HS, XW, JZ]; 4) Sigma Xi Grants in Aid Research [To PW]; and 5) We thank Jazzminn Hembree (Director of Laboratory Animal Resources, Miami University) and Laboratory Animal Resources, Dr. Jiangjiang Zhu (Department of Human Sciences, Ohio State University), Dr. Jing Zhang (Department of Statistics), and Dr. Ramiro Malgor (Director of Histology Core Facility, Ohio University) Citation Format: Prachi Wele, Haifei Shi, Xian Wu. Deciphering colorectal cancer: A model to study sex-based differences and role of estrogen amidst obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3393.