The Development and Application of Female Diet-Induced Obesity Models to Investigate GLP-1R/GIPR Agonist Effects on Breast Cancer

Abstract

Obesity has reached epidemic proportions in the United States and is associated with an increased risk of several cancers, including postmenopausal breast cancer. Regardless of menopausal status, obesity leads to worsened breast cancer progression due to its associations with systemic metabolism and inflammation, which affect the tumor microenvironment. Dietary interventions such as fasting, calorie restriction, and bariatric surgery have shown promise in improving outcomes and response to treatment for obese and lean patients, though their invasiveness and poor patient compliance limit clinical utility. Incretin agonist drugs, once confined to the treatment of Type 2 diabetes, have come to the forefront of public conversation for their remarkable ability to affect weight loss in overweight or obese patients; Tirzepatide, a dual-agonist of GLP-1 and GIP receptors, has been shown to be even more effective than earlier approved Semaglutide (GLP-1 agonist alone). To evaluate Tirzepatide as a metabolic therapy for breast cancer, a clinically relevant mouse model resembling the comorbidities associated with diet-induced obesity (DIO) is required. However, female DIO models are understudied due to delayed onset, high variability, and protective profiles of female mice compared to males. To combat this, fructose was administered in combination with a high-fat diet (HFD) for both its relevance to the Western diet and its indirect effect on weight gain by encouraging overconsumption. Fructose supplementation accelerated the onset and severity of obesity phenotypes in C57BL/6 and BALB/c models. FVB/N GEM models also responded well to HFD-feeding alone. C57BL/6 and BALB/c models were chosen for further tumor induction studies with EO771 or 4T07 triple-negative cell lines. HFD or HFD plus fructose (HFD + F) mice were given Tirzepatide injections either pre- or post-tumor inoculation. As well, mice on a purified control diet (PC) were similarly treated to observe the effects of the drug in a lean model. Though the experiment is ongoing, obese mice (HFD or HFD + F) treated with Tirzepatide show significant reductions in tumor burden, with outcomes comparable to lean controls. These findings support the utility of fructose in female DIO modeling and future investigations into Tirzepatide as a metabolic adjuvant therapy.