The effects of obesity and GLP-1R/GIPR agonists on early-onset breast cancer risk

PROJECT SUMMARY/ABSTRACT The global rise in early-onset breast cancer (EOBC), particularly in women under 40, is an urgent and poorly understood public health concern. EOBC often presents as aggressive subtypes in women without known genetic predispositions. While obesity is a well-established risk factor for postmenopausal breast cancer, its role in EOBC remains unclear. This gap is exacerbated by the lack of physiologically relevant preclinical models that integrate age, obesity, and mammary gland biology—factors critical to studying early tumorigenesis. Obesity is characterized by chronic low-grade inflammation and systemic metabolic dysfunction, both of which promote a tumor-supportive environment. Modulating these effects through calorie restriction, fasting, or bariatric surgery has shown promise, yet clinical translation is limited by adherence and sustainability. Recently, GLP- 1R/GIPR agonists have emerged as a safe and effective pharmacologic intervention for weight loss in obese patients. However, their potential to reverse obesity-driven cancer risk, especially in EOBC, remains largely unexplored. We hypothesize that diet-induced obesity accelerates mammary tumorigenesis in EOBC, and that GLP- 1R/GIPR agonists can mitigate this risk by restoring metabolic balance and reprogramming immune responses. Preliminary results demonstrate that obesity enhances tumor development, while treatment with the dual agonist tirzepatide reverses this effect. To test this, we will utilize two unique, immune-competent genetically engineered mouse models (GEMMs) developed in our lab that recapitulate HER2⁺ and triple-negative subtypes commonly seen in EOBC. These models allow precise temporal control of tumor initiation, aligned with the clinical window of disease onset in women. Aim 1 will define how obesity and GLP-1R/GIPR agonists affect tumor initiation, progression, and metastasis. Mice will be rendered obese via high-fat diet prior to tumor induction and randomized to receive tirzepatide or vehicle. Tumor dynamics will be tracked using bioluminescence imaging and ex vivo analyses. Aim 2 will uncover systemic and tumor-intrinsic mechanisms that mediate differential tumor responses across lean, obese, and weight-loss conditions using immunofluorescence, flow cytometry, and serum metabolomics. Together, these studies will elucidate the impact of obesity and weight-loss therapy in early-onset breast cancer risks and progression and pave the way toward understanding the underlying mechanisms thereof.