Context-dependent pharmacological effects of GLP-1 receptor agonists in breast cancer from molecular mechanisms to clinical safety

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become cornerstone therapeutics for type 2 diabetes mellitus and obesity, but their impact on breast cancer remains uncertain. Preclinical studies show context-dependent effects of GLP-1 RAs on breast-cancer cells. Direct evidence from breast-cancer models supports a pro-proliferative NADPH oxidase 4 (NOX4)/reactive oxygen species (ROS) /VEGF pathway under supra-pharmacological exposure, whereas PI3K/Akt-mediated pro-survival signaling and cAMP/PKA/CREB-driven proliferation remain inferred from non-breast systems and require direct confirmation. Under obesity- and insulin-resistant conditions, indirect antitumor effects may occur through improved insulin sensitivity, altered adipokines, and remodeling of the tumor immune microenvironment. Meta-analyses of randomized controlled trials do not show a significant increase in breast-cancer risk (RR 0.98, 95% CI 0.76-1.26), while some large observational cohorts report small risk differences that are susceptible to confounding and detection bias. Evidence for inter-agent differences is observational and limited by the absence of head-to-head randomized oncological comparisons. This narrative review synthesizes preclinical and clinical evidence across three dimensions, namely, molecular subtype, drug exposure, and host metabolic status, and distinguishes direct breast-cancer evidence from mechanistic extrapolation. We outline evidence-informed clinical considerations and research priorities rather than definitive recommendations.