Glucose Promotes Breast Cancer Aggression and Reduces Metformin Efficacy
Open accessAbstract
Metformin treatment has been associated with a decrease in breast cancer risk and improved survival. Metformin induces complex cellular changes, resulting in decreased tumor cell proliferation, reduction of stem cells, and apoptosis. Using a carcinogen-induced rodent model of mammary tumorigenesis, we recently demonstrated that overfeeding in obese animals is associated with a 50% increase in tumor glucose uptake, increased proliferation, and tumor cell reprogramming to an "aggressive" metabolic state. Metformin significantly inhibited these pro-tumorigenic effects. We hypothesized that a dynamic relationship exists between chronic energy excess (glucose by dose) and metformin efficacy/action. Media glucose concentrations above 5 mmol/L was associated with significant increase in breast cancer cell proliferation, clonogenicity, motility, upregulation/activation of pro-oncogenic signaling, and reduction in apoptosis. These effects were most significant in triple-negative breast cancer (TNBC) cell lines. High-glucose conditions (10 mmol/L or above) significantly abrogated the effects of metformin. Mechanisms of metformin action at normal vs. high glucose overlapped but were not identical; for example, metformin reduced IGF-1R expression in both the HER2+ SK-BR-3 and TNBC MDA-MB-468 cell lines more significantly at 5, as compared with 10 mmol/L glucose. Significant changes in gene profiles related to apoptosis, cellular processes, metabolic processes, and cell proliferation occurred with metformin treatment in cells grown at 5 mmol/L glucose, whereas under high-glucose conditions, metformin did not significantly increase apoptotic/cellular death genes. These data indicate that failure to maintain glucose homeostasis may promote a more aggressive breast cancer phenotype and alter metformin efficacy and mechanisms of action.
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Triple negative breast cancer cells (TNBC) are particularly sensitive to the pro-proliferative effects of glucose, and TNBC cells are more sensitive to metformin at lower levels of glucose.
“Studies of the effects of glucose concentration on the anti-proliferative effects of metformin on breast cancer cell growth in different human cancer lines In vitro studies reveal that triple negative breast cancer cells (TNBC) are particularly sensitive to the pro-proliferative effects of glucose, and TNBC cells are more sensitive to metformin at lower levels of glucose (250).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [250]
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- Authors
- Wahdan-Alaswad, R., Fan, Z., Edgerton, S. M., Liu, B., Deng, X.-S., Arnadottir, S. S., Richer, J. K., Anderson, S. M., & Thor, A. D.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Thor, Ann D
- ORCID
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2013-12-15
- Volume
- 12
- Issue
- 24
- Pages
- 3759-3769
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC3905068
- OpenAlex
- W1995532066
- Cited by
- 125
- References
- 60
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 10 · 2023: 10 · 2022: 9 · 2021: 8 · 2020: 19 · 2019: 12 · 2018: 9 · 2017: 11 · 2016: 10 · 2015: 12 · 2014: 12
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen
- National Institutes of Health (2p01hd038129-11a1)
- National Cancer Institute (P30CA043934, P30CA046934)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD-038129)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- metformin, breast cancer, high glucose, glucose homeostasis, triple-negative breast cancer, IGF-1 receptor, tumor cell proliferation, apoptosis, tumor cell motility, tumor aggressiveness, metabolic reprogramming, obesity, drug resistance
- MeSH terms
- Breast Neoplasms, Cell Cycle, Female, Glucose, Humans, Hypoglycemic Agents, Metformin, Signal Transduction, Apoptosis, Cell Line, Tumor, Cell Proliferation
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