MON-325 Tirzepatide Improves Metabolic Dysfunction in High-Fat Diet-Fed Brca1+/- Mice

Abstract Disclosure: S. Palikhe: None. L. Qiao: None. P. Dhorajiya: None. P. Bhardwaj: None. C. Kutz: None. K. McCartney: None. J.P. Thyfault: None. K.A. Brown: None. Tirzepatide, a dual agonist for glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, induces significant weight loss and improves metabolic health in individuals with type 2 diabetes and obesity. In preclinical models, tirzepatide has shown benefits in glucose tolerance, insulin sensitivity, and reducing hepatic steatosis under a high-fat diet (HFD). Epidemiological studies have shown that obesity and metabolic dysfunction are strongly associated with increased breast cancer risk, including in BRCA1 mutation carriers. We previously demonstrated that obesity and markers of poor metabolic health exacerbate DNA damage in the mammary epithelium of BRCA1 mutation carriers and accelerate DMBA/MPA-induced mammary tumor development in HFD-fed Brca1 heterozygous knockout (Brca1+/-) mice compared to low-fat diet-fed mice. In this study, we hypothesized that tirzepatide treatment could delay or prevent mammary tumor development in HFD-fed Brca1+/- mice by alleviating metabolic dysfunction and thus reducing DNA damage in mammary epithelium. We found that HFD-fed Brca1+/-mice treated with tirzepatide exhibited significant reductions in body weight gain, fat mass, and food intake compared to vehicle-treated controls. Tirzepatide also improved glucose tolerance and markedly reduced hepatic steatosis. These findings highlight tirzepatide potential to mitigate HFD-induced metabolic dysfunction in Brca1+/- mice, laying the groundwork for future studies exploring its role in reducing mammary tumor formation in this high-risk population. Presentation: Monday, July 14, 2025