The DOI matches its Crossref record; 51 of the 55 references it cites were found in a registry or an index.
The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells
Open accessAbstract
Population studies have revealed that treatment with the antidiabetic drug metformin significantly associates with reduced breast cancer risk. Animal studies have shown that metformin suppresses the development of mammary carcinomas in transgenic female mice carrying a HER2 oncogene, but not that of spontaneous tumors. We herein demonstrate that HER2 oncoprotein itself may represent a key cellular target involved in the anti-breast cancer actions of metformin. First, ectopical overexpression of HER2 oncogene significantly enhances metformin-induced breast cancer cell growth inhibition. Second, metformin treatment drastically downregulates HER2 protein levels (up to 85% reduction) in a dose- and time-dependent manner. Metformin-induced inhibition of HER2 take places regardless the molecular mechanism contributing to HER2 overexpression (i.e., human HER2 cDNA exogenously driven by a viral promoter and naturally occurring endogenous HER2 gene amplification). Mechanistically, metformin-induced suppression of HER2 overexpression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity. Compound C- and small interference RNA (siRNA)-induced blockade of AMPK activity/expression fail to prevent the anti-HER2 effect of metformin while AMPK hyperactivation following exposure to the AMP analog AICAR is not sufficient to downregulate HER2 expression. HER2-positive breast cancer cells transfected with p70S6K1 siRNA become completely refractory to metformin-induced HER2 suppression. Of note, co-incubation with agents that block reactive oxygen species (ROS) production (e.g., N-acetylcysteine) dramatically enhanced the ability of metformin to decrease HER2 expression. From the perspective of chemoprevention, these findings altogether suggest that metformin might exert a protective mostly confined to the HER2-positive breast cancer subtype. From the perspective of intervention, the presence/absence of molecular hallmarks such as HER2 overexpression and/or p70S6K1 hyperactivation might dictate alternative responses in metformin-based treatment of early breast cancer. The importance of mTOR/p70S6K1-sensed ROS status at mediating the anti-oncogenic effects of metformin might represent a previously unrecognized linkage molecularly connecting its anti-aging and anti-cancer actions.
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“Other in vitro studies suggest that metformin may selectively kill cancer stem cells and enhance effectiveness of breast cancer treatment regimens (85–87).”
From Diabetes and Cancer (2010) · cites this paper as [85]
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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
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Self-citationMetformin and reduced risk of cancer in diabetic patients
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“15-25 Interestingly, the ability of metformin to drastically downregulate HER2 oncoprotein expression appears to work independently of AMPK when considering the following findings: (1) Compound C, an inhibitor of AMPK, does not entirely prevent the downregulation of HER2 occurring upon metformin treatment; (2) the AMP…”
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Energy-dependent regulation of cell structure by AMP-activated protein kinase
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4 of the 55 references couldn’t be matched to a known paper.
Research works printed but not linked: 7
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Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G., & Yee, D. (2010) · Diabetes Care · doi:10.2337/dc10-0666 · Cited by 2,366
Cellular and molecular mechanisms of metformin: an overview
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Diabetes and Cancer: A Consensus Report
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Wolin, K. Y., Carson, K., & Colditz, G. A. (2010) · The Oncologist · doi:10.1634/theoncologist.2009-0285 · Cited by 778
Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
Rojas, L. B. A., & Gomes, M. B. (2013) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-5-6 · Cited by 567
“Some of these mechanisms may be through inhibition of cell growth [148], IGF-1 signaling [149], inhibition of the mTOR pathway [150], reduction of human epidermal growth factor receptor type 2 (HER-2) expression (a major driver of proliferation in breast cancer) [151], inhibition of angiogenesis and inflammation [152]…”
Background
Metadata
- Authors
- Vazquez-Martin, A., Oliveras-Ferraros, C., & Menendez, J. A.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-01
- Volume
- 8
- Issue
- 1
- Pages
- 88-96
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W1974130263
- Cited by
- 250
- References
- 55
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 15 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 11 · 2017: 19 · 2016: 11 · 2015: 24 · 2014: 15 · 2013: 22 · 2012: 17
- FWCI
- 11.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen for the Cure
- Susan G. Komen
- Fundación Científica Asociación Española Contra el Cáncer (CP05-00090, PI06-0778, RD06-0020-0028)
- Instituto de Salud Carlos III (RD06-0020-0028, CP05-00090, PI06-0778)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- metformin, HER2 overexpression, p70S6K1, mTOR signaling, breast cancer, chemoprevention, AMPK-independent mechanism, reactive oxygen species, N-acetylcysteine, siRNA knockdown, AICAR, HER2-positive breast cancer, drug repurposing
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Breast Neoplasms, Cell Survival, Dose-Response Relationship, Drug, Enzyme Activation, Female, Humans, Hypoglycemic Agents, Metformin, Protein Kinases, Time Factors, Erb-b2 Receptor Tyrosine Kinases, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, Cell Proliferation, TOR Serine-Threonine Kinases
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