Tirzepatide attenuates mammary tumor progression in diet-induced obese mice

Abstract

We report for the first time an anticancer benefit of tirzepatide-a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist-in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.

Keywords: Breast cancer; incretin therapeutics; obesity; tirzepatide.

Figure 1.. Study design.

Schematic of study conducted to assess the potential of tirzepatide treatment to ameliorate tumor growth in a murine model of diet-induced obesity and triple-negative breast cancer. CCR, chronic calorie restriction; DIO, diet-induced obesity; TZP, tirzepatide. Created with BioRender.com.

Figure 2.. Chronic tirzepatide treatment reduces food intake, body weight, fat stores, and mammary tumor growth in obese female mice.

(A) Body weight change and (B) cumulative food intake/mouse across 13-week intervention. (C) Body weight, (D) lean mass, (E) fat mass, and (F) percent fat and lean mass, at week 9 of the weight loss intervention. (G) Orthotopic E0771 tumor mass after 4 weeks of growth. (H) Correlation between terminal body weight and tumor mass. Error bars indicate mean±SD. Repeated measures two-way ANOVA with Šídák’s multiple comparisons test used for A. Unpaired t-test used for B. One-way ANOVA with Tukey’s post hoc test used for C-G. Spearman correlation used for H. A-C,G: Control n=14, DIO n=15, TZP n=13, CCR n=15; D-F: n=10/group; H: n=57. Different letters denote p≤0.05 between groups. AUC, area under the curve; CCR, chronic calorie restriction; DIO, diet-induced obesity; TZP, tirzepatide.