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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Metformin may selectively kill cancer stem cells and enhance effectiveness of breast cancer treatment regimens.
“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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“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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Obesity and cancer: mechanistic insights from transdisciplinary studies
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“Many groups have demonstrated metformin’s action in vitro in a variety of cancer types [10–14].”
BackgroundTargeted Therapy for Breast Cancer Prevention
den Hollander, P., Savage, M. I., & Brown, P. H. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00250 · Cited by 156 · see citing works
“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).”
BackgroundMetformin Targets Multiple Signaling Pathways in Cancer
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 · see citing works
The effect of environmental chemicals on the tumor microenvironment
Casey, S. C., Vaccari, M., Al‐Mulla, F., Al-Temaimi, R. A., Amedei, A., Barcellos‐Hoff, M. H., Brown, D. G., Chapellier, M., Christopher, J., Curran, C. S., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv035 · Cited by 155 · see citing works
“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
Hurvitz, S. A., Hu, Y., O’Brien, N. A., & Finn, R. S. (2012) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2012.04.008 · Cited by 151 · see citing works
“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…”
BackgroundInfluentialLiu, B., Fan, Z., Edgerton, S. M., Yang, X., Lind, S. E., & Thor, A. D. (2011) · Cell Cycle · doi:10.4161/cc.10.17.16359 · Cited by 146 · see citing works
“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 · see citing works
Metformin for aging and cancer prevention
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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].”
BackgroundMetformin targets c-MYC oncogene to prevent prostate cancer
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 · see citing works
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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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“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 118 · see citing works
“Metformin has been shown to exhibit antiproliferative and antineoplastic effects associated with the inhibition of mammalian target of rapamycin complex 1 (mTORC1) [91-94].”
BackgroundSelf-citationObesity, Inflammation, and Postmenopausal Breast Cancer: Therapeutic Implications
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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 110 · see citing works
“, 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.”
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“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 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
Margel, D., Urbach, D. R., Lipscombe, L. L., Bell, C. M., Kulkarni, G. S., Austin, P. C., & Fleshner, N. E. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt170 · Cited by 91 · see citing works
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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 · see citing works
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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Leptin and Adiponectin: Emerging Therapeutic Targets in Breast Cancer
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“Interestingly, in HER2 models, metformin reduces HER2 expression via AMPK-independent inhibition of p70S6K1 activity [143].”
BackgroundMetformin: The hidden chronicles of a magic drug
Mahmood, K., Naeem, M., & Rahimnajjad, N. A. (2012) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2012.10.011 · Cited by 79 · see citing works
“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
Clements, A., Gao, B., Yeap, S. H., Wong, M. K., Ali, S. S., & Gurney, H. (2011) · Annals of Oncology · doi:10.1093/annonc/mdr037 · Cited by 80 · see citing works
Hormesis does not make sense except in the light of TOR-driven aging
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Self-citationCancer Risk in HBV Patients With Statin and Metformin Use
Chen, C.-I., Kuan, C.-F., Fang, Y.-A., Liu, S., Liu, J., Wu, L., Chang, C.-J., Yang, H., Hwang, J., Miser, J. S., et al. (2015) · Medicine · doi:10.1097/md.0000000000000462 · Cited by 76 · see citing works
Metformin impairs the growth of liver kinase B1-intact cervical cancer cells
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“Further, metformin can induce cell cycle arrest and decrease the oncoprotein level of epidermal growth factor receptor 2 (Her2) in breast and pancreatic cancer cells, respectively [32–36].”
BackgroundZhou, X., Xue, W., Ding, X., Li, L., Dou, M., Zhang, W., Lv, Z., Fan, Z., Zhao, J., & Wang, L. (2017) · Oncotarget · doi:10.18632/oncotarget.16973 · Cited by 75 · see citing works
“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
Wysocki, P. J., & Wierusz‐Wysocka, B. (2010) · Expert Review of Molecular Diagnostics · doi:10.1586/erm.10.22 · Cited by 72 · see citing works
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Metformin as an antitumor agent in cancer prevention and treatment
Li, D. (2011) · Journal of Diabetes · doi:10.1111/j.1753-0407.2011.00119.x · Cited by 68 · see citing works
Health benefits of late-onset metformin treatment every other week in mice
Alfaras, I., Mitchell, S. J., Mora, H., Lugo, D. R., Warren, A., Navas-Enamorado, I., Hoffmann, V., Hine, C., Mitchell, J. R., Le Couteur, D. G., et al. (2017) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-017-0018-7 · Cited by 68 · see citing works
Vazquez-Martin, A., López-Bonetc, E., Cufí, S., Oliveras-Ferraros, C., Del Barco, S., Martin-Castillo, B., & Menendez, J. A. (2011) · Drug Resistance Updates · doi:10.1016/j.drup.2011.04.003 · Cited by 66 · see citing works
“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 64 · see citing works
“[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.”
BackgroundMartı́n-Castillo, B., Dorca, J., Vázquez‐Martín, A., Oliveras‐Ferraros, C., López‐Bonet, E., García, M., del Barco, S., & Menéndez, J. A. (2009) · Annals of Oncology · doi:10.1093/annonc/mdp494 · Cited by 63 · see citing works
Self-citationTargeting the LKB1 Tumor Suppressor
Zhao, R., & Xu, Z. (2014) · Current Drug Targets · doi:10.2174/1389450114666140106095811 · Cited by 61 · see citing works
Metformin-induced anticancer activities: recent insights
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“, 2013); and also ErbB2 in breast cancer cells (Vazquez-Martin et al., 2009).”
BackgroundOchoa-González, F. D. L., Cervantes-Villagrana, A. R., Fernández-Ruiz, J. C., Nava-Ramirez, H. S., Hernandez-Correa, A. C., Enciso‐Moreno, J. A., & Castañeda‐Delgado, J. E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150900 · Cited by 63 · see citing works
Vázquez‐Martín, A., Oliveras‐Ferraros, C., Barco, S. D., Martı́n-Castillo, B., & Menéndez, J. A. (2009) · Clinical & Translational Oncology · doi:10.1007/s12094-009-0384-0 · Cited by 60 · see citing works
Self-citationWestley, R., & May, F. E. B. (2013) · International Journal of Endocrinology · doi:10.1155/2013/632461 · Cited by 59 · see citing works
Andújar-Plata, P., Pi-Sunyer, X., & Laferrère, B. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.09.022 · Cited by 58 · see citing works
“However, metformin may act by other mechanisms because it still has some effect when an AMPK inhibitor is used [59].”
BackgroundGerosuppressant Metformin: less is more
Menéndez, J. A., Cufí, S., Oliveras‐Ferraros, C., Vellón, L., Joven, J., & Vázquez‐Martín, A. (2011) · Aging · doi:10.18632/aging.100316 · Cited by 57 · see citing works
“Metformin exposure efficiently suppresses S6K1 activity in cultured proliferating epithelial cells [21-23].”
BackgroundSelf-citationMetabolism and immunity in breast cancer
Zhang, D., Xu, X., & Ye, Q. (2020) · Frontiers of Medicine · doi:10.1007/s11684-020-0793-6 · Cited by 58 · see citing works
Barbieri, F., Thellung, S., Ratto, A., Carra, E., Marini, V., Fucile, C., Bajetto, A., Pattarozzi, A., Würth, R., Gatti, M., et al. (2015) · BMC Cancer · doi:10.1186/s12885-015-1235-8 · Cited by 59 · see citing works
“However, in all these studies the effects of metformin, alone or in combination with doxorubicin or trastuzumab, were mainly evaluated in CSClike derived from established lines [49-51].”
BackgroundSoo, J. S.-S., Ng, C., Tan, S. H., Malik, R. A., Teh, Y.-C., Tan, B.-S., Ho, G. F., See, M., Taib, N. A. M., Yip, C. H., et al. (2015) · APOPTOSIS · doi:10.1007/s10495-015-1158-5 · Cited by 58 · see citing works
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Metformin: A Dual-Role Player in Cancer Treatment and Prevention
Galal, M. A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S. S., & Aljada, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074083 · Cited by 68 · see citing works
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“Human epidermal growth receptor 2 (HER2) oncogene was also found to significantly enhance metformin induced breast cancer cell inhibition in both AMPK dependent and AMPKindependent pathways [114].”
BackgroundKong, G., Zhou, L., Serger, E., Palmisano, I., Virgiliis, F. D., Hutson, T. H., McLachlan, E., Freiwald, A., Montanara, P. L., Shkura, K., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0252-3 · Cited by 53 · see citing works
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“At present, it is also known that some of metformin biological responses are not limited to activation of AMPK but mediated by AMPK-independent mechanisms including inhibition of such different cellular targets as p70S6K1 (Vazquez-Martin et al. 2009), p38 mitogenactivated protein kinase, and protein kinase C (Saeedi e…”
BackgroundNCI's provocative questions on cancer: some answers to ignite discussion
Blagosklonny, M. V. (2011) · Oncotarget · doi:10.18632/oncotarget.432 · Cited by 51 · see citing works
“Metformin, an anti-diabetic drug, inhibits the mTOR pathway [197-200].”
BackgroundMolecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer
Thompson, A. M. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0354 · Cited by 50 · see citing works
Prospective study of a diabetes risk reduction diet and the risk of breast cancer
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“Metformin can suppress HER2 protein overexpression (96) and delay cancer onset in animal models (97), and it was associated with reduced risk of fatal HER2-positive breast cancer (95).”
BackgroundChang, Y., Tsai, H., Kung, Y.-T., Yeh, Y., Huang, C., Ma, C., Chiu, H., & Wang, J. (2018) · Translational Oncology · doi:10.1016/j.tranon.2018.02.012 · Cited by 52 · see citing works
“At low doses (in the micromolar range), the tyrosine kinase activity of HER2 is blocked, but its expression levels are unaffected, whereas at higher concentrations (in the millimolar range), HER2 protein expression is down-regulated [24].”
BackgroundAMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications
Vakana, E., & Platanias, L. C. (2011) · Oncotarget · doi:10.18632/oncotarget.413 · Cited by 48 · see citing works
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The effect of metformin on breast cancer outcomes in patients with type 2 diabetes
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“metformin include inhibition of phosphorylation of IGF1R/IR [17], inhibition of aromatase expression [18], and reduction in HER2 expression and its tyrosine kinase activity [14, 19].”
BackgroundFujihara, S., Kato, K., Morishita, A., Iwama, H., Nishioka, T., Chiyo, T., Nishiyama, N., Miyoshi, H., Kobayashi, M., Kobara, H., et al. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.2903 · Cited by 46 · see citing works
“These properties can result in the inhibition of cancer cell growth, the suppression of hER2 overexpression and the inhibition of mTOR (24-26).”
BackgroundRegulation of insulin-like growth factor signaling by metformin in endometrial cancer cells
XIE, Y., WANG, J.-L., JI, M., YUAN, Z.-F., PENG, Z., ZHANG, Y., WEN, J.-G., & SHI, H.-R. (2014) · Oncology Letters · doi:10.3892/ol.2014.2466 · Cited by 46 · see citing works
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“[37] found that metformin suppresses HER2 oncoprotein expression, and HER2 overexpression enhances metformin-induced breast cancer cell growth inhibition.”
Background
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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