Context-dependent pharmacological effects of GLP-1 receptor agonists in breast cancer from molecular mechanisms to clinical safety
4 affiliations
- 1Department of Clinical Laboratory, The Central Hospital of Qinghe County
- 2Department of Pathogen Biology, Guizhou Nursing Vocational College
- 3Department of Clinical Laboratory, Zunyi Hospital of Traditional Chinese Medicine
- 4Medical Affairs Department, The Second Affiliated Hospital of Zunyi Medical University
Abstract
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.
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BibTeX
@article{xie2026contextdependent,
title = {{Context-dependent pharmacological effects of GLP-1 receptor agonists in breast cancer from molecular mechanisms to clinical safety}},
author = {Zhen-yu Xie and Yue Qian and Ting-ting Liu and Ping Xiang and Ying Mu and Wei Zhang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1978397},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1978397/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Context-dependent pharmacological effects of GLP-1 receptor agonists in breast cancer from molecular mechanisms to clinical safety
AU - Zhen-yu Xie
AU - Yue Qian
AU - Ting-ting Liu
AU - Ping Xiang
AU - Ying Mu
AU - Wei Zhang
PY - 2026
DA - 2026/10/28
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1978397
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1978397/full
AB - 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.
SN - 1663-9812
ER -