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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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“In addition to its effects on cell cycle, metformin can interfere with some receptors, because metformin decreases the oncoprotein level of Her2 (erbB-2) or epidermal growth factor receptor in breast and pancreatic cancer cells, respectively (36, 37).”
BackgroundBiguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling
Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Köhler, A., Glossmann, H., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912793107 · Cited by 380
“The anti-type II diabetes drug metformin has been shown to inhibit mTOR activity (22, 23).”
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“It is also known that some of the biological responses to metformin are not limited to the activation of AMPK, but are mediated by AMPK-independent mechanisms, including inhibition of such different cellular targets as p70S6K1 [27], p38 mitogen-activated protein kinase (p38 MAPK), and protein kinase C [25].”
Metformin induces unique biological and molecular responses in triple negative breast cancer cells
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Metformin: Taking away the candy for cancer?
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“This effect was mediated by inhibition of the mTOR effector, p70S6K1 (34).”
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Barco, S. D., Vázquez‐Martín, A., Cufí, S., Oliveras‐Ferraros, C., Bosch‐Barrera, J., Joven, J., Martı́n-Castillo, B., & Menéndez, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.387 · Cited by 307
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“Moreover, there is evidence that insulin and IGF-1 may also be relevant to dietary habits and lifestyle, which influence cancer risk and prognosis, probably starting from early tumour initiation events (53).”
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Kourelis, T., & Siegel, R. D. (2011) · Medical Oncology · doi:10.1007/s12032-011-9846-7 · Cited by 294
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Repositioning metformin for cancer prevention and treatment
Quinn, B. J., Kitagawa, H., Memmott, R. M., Gills, J. J., & Dennis, P. A. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.05.004 · Cited by 290
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“Metformin has a number of additional cellular activities that have potential antineoplastic activity including AMP-kinase pathway activation [6, 7], p-53 activation [8], downregulation of cyclin D1 [7, 9], and suppression of HER2 oncoprotein expression [6].”
BackgroundInfluentialMetformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With Diabetes
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“Metformin can induce AMP-activated protein kinase (AMPK) phosphorylation, protein kinase c and Mitogen-activated protein kinase directly (Vazquez-Martin et al. 2009).”
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Metformin and Other Biguanides in Oncology: Advancing the Research Agenda
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The role of mTOR signaling in Alzheimer disease
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“Indeed, experiments in primary neurons and mice have shown that blocking mTOR activity with metformin, an mTOR inhibitor (82, 83), induces PP2A activity and reduces tau phosphorylation at three PP2Adependent epitopes, Ser202, Ser356, and Ser262 (84).”
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Godsland, I. F. (2009) · Clinical Science · doi:10.1042/cs20090399 · Cited by 233
Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis
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“It is well established that metformin exerts antiproliferative effects on cancer cells in vitro [17,22,23]; however, the mechanisms of metformin action on tumor cells are poorly understood.”
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The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus
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“Many groups have demonstrated metformin’s action in vitro in a variety of cancer types [10–14].”
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“Metformin has also been shown to activate AMP-activated protein kinase (AMPK) (Figure 1), which recent studies suggest may overcome resistance to HER2 inhibitors (88).”
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Lei, Y., Yi, Y., Liu, Y., Liu, X., Keller, E. T., Qian, C.-N., Zhang, J., & Lu, Y. (2017) · Chinese Journal of Cancer · doi:10.1186/s40880-017-0184-9 · Cited by 152
The effect of environmental chemicals on the tumor microenvironment
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“Metformin can modulate the cancer inflammatory microenvironment (145,146), inhibit neoplastic angiogenesis, decrease VEGF and plasminogen activator inhibitor-1 levels (147,148), inhibit human epidermal growth factor receptor-2 expression via p70S6K1 activity inhibition (149), induce cell cycle arrest (150), promote bo…”
BackgroundCurrent approaches and future directions in the treatment of HER2-positive breast cancer
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“This therapy was well tolerated by patients and boosted patients’ immunity in a sustained pattern.109 Metformin Metformin is an antidiabetic biguanide agent that is associated with a reduced risk of developing BC.110 One action of metformin is to activate adenosine monophosphate-activated protein kinase, which promote…”
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“Therapeutic potential of metformin for women with erbB2overexpressing breast cancers has been suggested by in vitro data showing a reduction of erbB2 tyrosine kinase activity, even at low concentrations of the drug.(16,18,36) A recent in vitro study has suggested that metformin may also interact significantly with oth…”
BackgroundAntidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease
Donadon, V., Balbi, M., Ghersetti, M., Grazioli, S., Perciaccante, A., Valentina, G. D., Gardenal, R., Mas, M. D., Casarin, P., Zanette, G., et al. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.2506 · Cited by 145
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“Data on molecular mechanisms of inhibitory effect of biguanides on tumor growth have been discussed in several recent papers [49-51,101,102,130-137].”
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Akinyeke, T. O., Matsumura, S., Wang, X., Wu, Y., Schalfer, E. D., Saxena, A. D., Yan, W., Logan, S. K., & Li, X. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt307 · Cited by 138
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“Also, metformin inhibits the mTOR pathway in cell culture [41-43].”
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“Moreover, metformin has been shown to inhibit the activation of the p70S6K pathway independently of AMPK (Vazquez-Martin et al., 2009) in tumour cells and p70S6K has been shown to be required for the growth hormone-dependent adipose conversion of 3T3-F442A preadipocytes (Yarwood et al.”
BackgroundMetformin and neoplasia: Implications and indications
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Morgillo, F., Sasso, F. C., Corte, C. M. D., Vitagliano, D., D’Aiuto, E., Troiani, T., Martinelli, E., Vita, F. D., Orditura, M., Palma, R. D., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2777 · Cited by 121
“mTOR exerts its effects by phosphorylating the eukaryotic initiation factor 4E binding protein 1 (4EBP1) and via the ribosomal protein S6 kinase (S6K, formerly known as p70s6K) (21).”
BackgroundCorominas-Faja, B., Quirantes‐Piné, R., Oliveras‐Ferraros, C., Vázquez‐Martín, A., Cufí, S., Martı́n-Castillo, B., Micol, V., Joven, J., Segura‐Carretero, A., & Menéndez, J. A. (2012) · Aging · doi:10.18632/aging.100472 · Cited by 121
“Metformin has been shown to exhibit antiproliferative and antineoplastic effects associated with the inhibition of mammalian target of rapamycin complex 1 (mTORC1) [91-94].”
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“Also, metformin-induced reduction of HER-2 protein expression in human breast cancer cells is mediated by inhibition of mTOR [69].”
BackgroundJanjetović, K., Vucicevic, L. M., Misirkic-Marjanovic, M., Vilimanovich, U., Tovilović-Kovačević, G., Zogovic, N. S., Nikolić, Z., Jovanović, S., Bumbasirevic, V. Z., Trajković, V., et al. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.11.005 · Cited by 115
“, 2009), inhibition of HER2 oncoprotein overexpression in breast cancer cells (Vazquez-Martin et al., 2009) and fatty acid oxidation and glucose utilization in the heart (Saeedi et al.”
Wang, J., Li, G., Wang, Y., Tang, S., Sun, X., Feng, X., Li, Y., Bao, G., Li, P., Mao, X., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6373 · Cited by 114
“This possibility is supported by the fact that metformin drastically down-regulated HER2 protein levels regardless of the molecular mechanism contributing to the HER2 overexpression [34].”
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Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy
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Metformin and Prostate Cancer: a New Role for an Old Drug
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“Metformin is a first-line medication for type 2 diabetes that can active the 50-AMP-activated protein kinase (AMPK) and down regulate the expression of the mammalian target of rapamycin (mTOR), which inhibits cell proliferation [18, 26, 27].”
BackgroundAssociation Between Metformin Use and Risk of Prostate Cancer and Its Grade
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Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells
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Metformin Selectively Targets Tumor-Initiating Cells in ErbB2-Overexpressing Breast Cancer Models
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“Mechanisms of metformin-mediated antitumor activities have been studied in different cell line models, and the derived data indicate that LKB1/AMPK/mTOR/ p70S6K pathway (39) and ErbB2 expression are the major functional targets of metformin (41).”
BackgroundClinical Outcomes After Radical Prostatectomy in Diabetic Patients Treated With Metformin
Patel, T., Hruby, G. W., Badani, K. K., Abate-Shen, C. T., & McKiernan, J. M. (2010) · Urology · doi:10.1016/j.urology.2010.03.059 · Cited by 85
RETRACTED: Metformin and Breast Cancer: Where Are We Now?
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Self-citationRetractedInvolvement of Akt-1 and mTOR in Sensitivity of Breast Cancer to Targeted Therapy
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“Interestingly, in HER2 models, metformin reduces HER2 expression via AMPK-independent inhibition of p70S6K1 activity [143].”
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“Metformin-induced suppression of HER2 over expression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity [95].”
BackgroundMetformin in prostate cancer: two for the price of one
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Hormesis does not make sense except in the light of TOR-driven aging
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“Regarding the mechanism underlying the anti-cancer effects of metformin, Kalender [49] showed that metformin disrupted mitochondrial energetics and inhibited mTORC1 kinase through an unknown mechanism, and Vazquez [50] showed that metformin reduces gluconeogenesis in the liver while promoting fat and muscle glucose up…”
BackgroundObesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin
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“Thus, metformin’s ability to decrease ERBB2 tyrosine kinase activity (Alimova et al., 2009) and ERBB2 oncoprotein expression (Vazquez-Martin et al., 2009a,b) might be highly effective against full malignant transformation by simultaneously targeting invasion, motility, and senescence in…”
BackgroundIkhlas, S., & Ahmad, M. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.07.029 · Cited by 66
“[89] showed that metformin efficiently obstructs human epidermal growth receptor 2 (HER2) oncogene overexpression as it inhibits p70S6K1 in MCF7 and SKBR3 breast cancer cell lines.”
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“[37] found that metformin suppresses HER2 oncoprotein expression, and HER2 overexpression enhances metformin-induced breast cancer cell growth inhibition.”
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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