Hormonal Influence on Breast Cancer Progression
5 affiliations
- 1Department of Biological Sciences, Midnapore City College, Midnapore 721129, West Bengal, India
- 2Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
- 3Department of Neurological Science, Rush University School of Medicine, Chicago, IL 60612, USA
- 4HIV Dynamics and Replication Program, National Institutes of Health, Frederick, MD 21702, USA
- 5Department of Natural Sciences, Hostos College of The City University of New York, Bronx, NY 10451, USA
Abstract
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.
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BibTeX
@article{de2026hormonal,
title = {{Hormonal Influence on Breast Cancer Progression}},
author = {Kamalendu De and Gloria M. Calaf and Malabendu Jana and Bhabadeb Chowdhury and Leodan A. Crispin and Debasish Roy},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110002},
url = {https://www.mdpi.com/1422-0067/27/21/10002},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hormonal Influence on Breast Cancer Progression
AU - Kamalendu De
AU - Gloria M. Calaf
AU - Malabendu Jana
AU - Bhabadeb Chowdhury
AU - Leodan A. Crispin
AU - Debasish Roy
PY - 2026
DA - 2026/11/08
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110002
UR - https://www.mdpi.com/1422-0067/27/21/10002
AB - 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.
SN - 1422-0067
ER -