Hormonal Influence on Breast Cancer Progression

Breast cancer remains a leading cause of cancer-related mortality among women worldwide. Beyond classical estrogen receptor-alpha (ERα) and progesterone receptor (PR) signaling, tumor progression, invasion, and treatment resistance are increasingly linked to an interconnected endocrine–metabolic network involving insulin, insulin-like growth factors (IGF-1/IGF-2), thyroid hormones (T3/T4), catecholamines, adrenal steroids, prolactin, and growth hormone within the tumor microenvironment (TME). Following systematic searches of PubMed, Web of Science, and Scopus through September 2025, 141 primary and translational studies were evaluated in this narrative review. Evidence was categorized according to experimental context: in vitro models, animal xenografts and patient-derived xenografts, and human clinical or epidemiological studies. Endocrine–metabolic resistance was characterized as a mechanism through which tumor cells may circumvent ER/HER2-targeted therapies via hyperinsulinemia-associated insulin receptor/IGF-1R signaling, aerobic glycolysis, thyroid hormone-mediated receptor phosphorylation, and sympathetic/adrenergic remodeling of the TME. Hypoxia was associated with radioresistance, whereas reoxygenation enhanced radiosensitivity; trastuzumab emtansine (T-DM1) was recognized as having clinically relevant toxicities, including thrombocytopenia and hepatotoxicity; non-canonical progesterone signaling was considered in PR-negative and triple-negative breast cancer phenotypes; and PR downregulation was associated with anti-estrogen treatment. Resistance to single-receptor-targeted therapies may be promoted by redundant metabolic and neuroendocrine signaling. Improved therapeutic outcomes may require biomarker-guided combination strategies incorporating selective estrogen receptor degraders, CDK4/6, AKT, and PI3Kα inhibitors, antibody–drug conjugates, and metabolic interventions, including metformin and glycemic control.