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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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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
Menendez, J. A., & Lupu, R. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2222 · Cited by 2,941
Self-citationMetformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388 · cited 1×
“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…”
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4447 · Cited by 949
Dowling, R. J. O., Zakikhani, M., Fantus, I. G., Pollak, M., & Sonenberg, N. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2310 · Cited by 933
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F. (2008) · Oncogene · doi:10.1038/sj.onc.1211024 · Cited by 861
Energy-dependent regulation of cell structure by AMP-activated protein kinase
Lee, J. H., Koh, H., Kim, M.-J., Kim, Y., Lee, S. Y., Karess, R. E., Lee, S. H., Shong, M., Kim, J., Kim, J., et al. (2007) · Nature · doi:10.1038/nature05828 · Cited by 431
Accumulation of Metformin by Tissues of the Normal and Diabetic Mouse
Wilcock, C., & Bailey, C. J. (1994) · Xenobiotica · doi:10.3109/00498259409043220 · Cited by 418
Anisimov, V. N., Berstein, L. M., Egormin, P. A., Piskunova, T. S., Popovich, I. G., Zabezhinski, M. A., Kovalenko, I. G., Poroshina, T. E., Semenchenko, A. V., Provinciali, M., et al. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.07.007 · Cited by 402
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., Mcburnie, W., Fleming, S., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20080557 · Cited by 396
Flagged first, then by citations
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Research works printed but not linked: 7
- Hundal RS, Inzucchi SE. Metformin: new understandings, new uses. Drugs 2003; 63:1879-94.
- Hadad SM, Appleyard V, Thompson AM. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 2008; in press.
- Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 2002; 62:4132-41.
- Yoon S, Lee MY, Park SW, Moon JS, Koh YK, Ahn YH, et al. Upregulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem 2007; 282:26122-31.
- Chajès V, Cambot M, Moreau K, Lenoir GM, Joulin V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 2006; 66:5287-94.
- Liu LZ, Hu XW, Xia C, He J, Zhou Q, Shi X, et al. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and p70S6K1 in human ovarian cancer cells. Free Radic Biol Med 2006; 41:1521-33.
- Zhou Q, Liu LZ, Fu B, Hu X, Shi X, Fang J, et al. Reactive oxygen species regulate insulin- induced VEGF and HIF-1alpha expression through the activation of p70S6K1 in human prostate cancer cells. Carcinogenesis 2007; 28:28-37.
Cited by
Sorted by citations
Items 101–200 of 250
Role of p53 Family Proteins in Metformin Anti-Cancer Activities
Yi, Y., Zhang, W., Yi, J., & Xiao, Z. J. (2019) · Journal of Cancer · doi:10.7150/jca.30659 · Cited by 47
“At the molecular levels, metformin can inhibit mTOR signaling or suppress expression of cyclin D1 and ErbB2 (Her2) to inhibit breast cancer cell proliferation and growth[49-51] (Figure 1B).”
BackgroundTaylor, J. R., Lehmann, B. D., Chappell, W. H., Abrams, S. L., Steelman, L. S., & McCubrey, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.315 · Cited by 46
Oliveras‐Ferraros, C., Cufí, S., Vázquez‐Martín, A., Menendez, O. J., Bosch‐Barrera, J., Martı́n-Castillo, B., Joven, J., & Menéndez, J. A. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19252 · Cited by 43
Self-citationAnticancer Effects of Metformin and Its Potential Use as a Therapeutic Agent for Breast Cancer
Guppy, A., Jamal‐Hanjani, M., & Pickering, L. M. (2011) · Future Oncology · doi:10.2217/fon.11.49 · Cited by 42
Targeting p70S6K Prevented Lung Metastasis in a Breast Cancer Xenograft Model
Akar, U., Özpolat, B., Mehta, K., Lopez‐Berestein, G., Zhang, D., Ueno, N. T., Hortobágyi, G. N., & Arun, B. K. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-1025 · Cited by 43
“Suppression of HER2 overexpression by the antidiabetic drug metformin seems to occur through direct (adenosine 5′-monophosphate-activated protein kinase independent) inhibition of p70S6K activity (17).”
BackgroundDhingra, S., Rodriguez, M. E., Shen, Q., Duan, X., Stanton, M., Chen, L., Zhang, R., & Brown, R. E. (2010) · PubMed Central · Cited by 41
Vélez, J., Pan, R. A., Lee, J. T. C., Enciso, L. J., Suarez, M., Duque, J. E., Jaramillo, D., López, C., Morales, L., Bornmann, W. G., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.9843 · Cited by 41
Cao, X., Wen, Z., Wang, X., Li, Y., Liu, K., & Wang, X. (2017) · Journal of Cancer · doi:10.7150/jca.19750 · Cited by 40
“Other in vitro studies have reported similar findings that metformin may kill cancer cells, reduce the cancer burden and enhance the effectiveness of breast cancer treatment [44-46].”
BackgroundCorleto, K. A., Strandmo, J. L., & Giles, E. D. (2024) · Pharmaceuticals · doi:10.3390/ph17030396 · Cited by 48
“Metformin has shown the ability to block HER2 tyrosine kinase activity [24], and breast cancer cells with overexpression of HER2 have improved metformin-induced inhibition of cell growth [25].”
BackgroundYi, Y., Chen, D., Ao, J., Sun, S., Wu, M. C., Li, X., Bergholz, J. S., Zhang, Y., & Xiao, Z. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.769141 · Cited by 40
Antitumor effect of metformin on cholangiocarcinoma: In vitro and in vivo studies
Fujimori, T., Kato, K., Fujihara, S., Iwama, H., Yamashita, T., Kobayashi, K., Kamada, H., Morishita, A., Kobara, H., Mori, H., et al. (2015) · Oncology Reports · doi:10.3892/or.2015.4284 · Cited by 41
Lin, H., Kachingwe, B. H., Lin, H., Cheng, H. W., Uang, Y., & Wang, L. (2013) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1334 · Cited by 39
Lettieri‐Barbato, D., Vegliante, R., Desideri, E., & Ciriolo, M. R. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.02.003 · Cited by 39
“Furthermore, metformin was reported to decrease the expression of the oncoprotein HER2 (erbB-2) in human breast cancer cells via a direct and AMPK-independent inhibition of p70-S6 Kinase 1 (p70S6K1) (a downstream of mTORC1 signalling pathway) activity [123].”
BackgroundZimmermann, M., Don, A. S. A., Donaldson, M. S., Patriarchi, T., & Horne, M. C. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1243189 · Cited by 39
Guo, Z., Zhao, M., Howard, E. W., Zhao, Q., Parris, A. B., Ma, Z., & Yang, X. (2017) · Oncotarget · doi:10.18632/oncotarget.19466 · Cited by 38
“Importantly, the ErbB2+ breast cancer subtype has been reported to be more responsive than the ErbB2-negative subtype to metformin and other biguanides [29, 30].”
BackgroundHabib, A., Karmali, V., Polavarapu, R., Akahori, H., Nakano, M., Yazdani, S. K., Otsuka, F., Pachura, K., Davis, T., Narula, J., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.12.018 · Cited by 36
Mostafavi, S., Zalpoor, H., & Hassan, Z. M. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00356-2 · Cited by 41
“Inhibition of mTOR in metformin-treated breast carcinoma cells also downregulated HER2 (human epidermal growth factor receptor-2 HER2), in an AMPKindependent manner [109].”
BackgroundSnima, K. S., Jayakumar, R., & Lakshmanan, V. (2014) · Pharmaceutical Research · doi:10.1007/s11095-014-1425-0 · Cited by 37
Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts
Lipner, M. B., Marayati, R., Deng, Y., Wang, X., Raftery, L., O’Neil, B. H., & Yeh, J. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147113 · Cited by 35
“Other studies in breast and ovarian cancer cell lines have also found that the effects of metformin may be only partially dependent on AMPK activation [43, 44].”
BackgroundInfluentialSurvival of the fittest: Cancer challenges T cell metabolism
Franchina, D. G., HeFeng, F. Q., & Brenner, D. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.014 · Cited by 34
Vázquez‐Martín, A., Oliveras‐Ferraros, C., Barco, S. D., Martı́n-Castillo, B., & Menéndez, J. A. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.24.5456 · Cited by 35
Self-citationAMP-activated protein kinase and energy balance in breast cancer.
Zhao, H., Orhan, Y. C., Zha, X., Esencan, E., Chatterton, R. T., & Bulun, S. E. (2017) · Europe PMC (PubMed Central) · Cited by 35
Arbab, A. A. I., Lu, X., Abdalla, I. M., et al. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.661380 · Cited by 34
Does use of metformin protect against cancer in Type 2 diabetes mellitus?
Bo, S., Benso, A. S., Durazzo, M., & Ghigo, E. (2012) · Journal of Endocrinological Investigation · doi:10.1007/bf03345423 · Cited by 33
Metformin and HER2-positive breast cancer: Mechanisms and therapeutic implications
Bashraheel, S. S., Kheraldine, H., Khalaf, S., & Moustafa, A. A. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114676 · Cited by 34
Shen, Q., Stanton, M., Feng, W., Rodriguez, M. E., Ramondetta, L. M., Chen, L., Brown, R. E., & Duan, X. (2010) · PubMed Central · Cited by 33
mTOR inhibitors sensitize thyroid cancer cells to cytotoxic effect of vemurafenib
Hanly, E. K., Bednarczyk, R. B., Tuli, N. Y., Moscatello, A. L., Halicka, H. D., Li, J., Geliebter, J., Darżynkiewicz, Z., & Tiwari, R. K. (2015) · Oncotarget · doi:10.18632/oncotarget.4052 · Cited by 33
“Actions of metformin in cancer cells may also include reducing expression of key enzymes involved in fatty acid synthesis as well as membrane tyrosine kinase receptors [42-44].”
BackgroundXiao, Y.-T., Zhang, S., Hou, G., Zhang, X., Hao, X., & Zhang, J. (2013) · Tumor Biology · doi:10.1007/s13277-013-1270-5 · Cited by 32
“Moreover, metformin can activate adenosine monophosphate-activated protein kinase (AMPK), thereby inhibiting cell proliferation [19–21].”
BackgroundChen, H., Cook, L. S., Tang, M.-T. C., Hill, D. A., Wiggins, C. L., & Li, C. I. (2019) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-19-0291 · Cited by 35
Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies
Mamtimin, M., Pinarci, A., Han, C., Braun, A., Anders, H., Gudermann, T. W., & Mammadova‐Bach, E. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.869706 · Cited by 35
Shahbazi, R., Jafari-Gharabaghlou, D., Mirjafary, Z., et al. (2023) · Pharmacological Reports · doi:10.1007/s43440-023-00462-8 · Cited by 32
“Metformin acts at the molecular level by activating AMPK and inhibiting mTOR, HER2, and mitogenactivated protein kinase (MAPK), downregulating cyclin D1 and E2F1, as well as the NFκB pathway [23, 24].”
BackgroundKim, Y. H., Noh, R., Cho, S. Y., Park, S. J., Jeon, S. M., Shin, H. D., Kim, S. B., & Shin, J. E. (2015) · Intestinal Research · doi:10.5217/ir.2015.13.2.145 · Cited by 31
Hypoxia and Metastasis in Breast Cancer
Rundqvist, H., & Johnson, R. S. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_77 · Cited by 33
Donadon, V., Balbi, M., & Zanette, G. (2009) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.09.41 · Cited by 29
García-García, C., Fumarola, C., Navaratnam, N., Carling, D., & López‐Rivas, A. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.10.022 · Cited by 27
Metformin Treatment for the Prevention and/or Treatment of Breast/Mammary Tumorigenesis
Grossmann, M. E., Yang, D.-Q., Guo, Z., Potter, D. A., & Cleary, M. P. (2015) · Current Pharmacology Reports · doi:10.1007/s40495-015-0032-z · Cited by 28
Wang, H., Cheng, X. F., Zhang, L., Xu, S., Zhang, Q., & Lu, R. (2019) · Food & Function · doi:10.1039/c9fo00109c · Cited by 27
AMP-activated protein kinase modulators: a patent review (2006 – 2010)
Yun, H., & Ha, J. (2011) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2011.577069 · Cited by 28
“These include suppression of overexpressed oncoprotein HER2 in breast cancer cells [142], decrease in prostate tumor cell growth by influencing cyclin D1 levels [143], activation Yun & Ha”
BackgroundRocca, A., Cortesi, P., Cortesi, L., Gianni, L., Matteucci, F., Fantini, L., Maestri, A., Giunchi, D. C., Cavanna, L., Ciani, R., et al. (2021) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835920985632 · Cited by 23
The effect of metformin when combined with neoadjuvant chemotherapy in breast cancer patients
El-khayat, S. M., Abouegylah, M. L., Abdallah, D., Gowil, A. G., El-Enbaby, A., & Zahra, O. S. (2021) · Medical Oncology · doi:10.1007/s12032-021-01599-3 · Cited by 27
Diabetes, Metformin, and Breast Cancer: Lilac Time?
Goodwin, P. J., Thompson, A. M., & Stambolic, V. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.3319 · Cited by 26
Insulin resistance and cancer: molecular links and clinical perspectives
Caturano, A., Erul, E., Nilo, R., Nilo, D., Russo, V., Rinaldi, L., Acierno, C., Gemelli, M. T., Ricotta, R., Sasso, F. C., et al. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05245-8 · Cited by 27
“…AMPK activation, mTOR pathway inhibition, IGF-1 signaling suppression, direct inhibition of mitochondrial complex I, epigenetic modulation, including reduced expression of oncogenic microRNAs and enhancement of tumor suppressor pathways, and HER2 suppression, which may slow tumor progression [201].”
Xing, X., Wu, K., Dong, Y., Zhou, Y., Zhang, J., Jiang, F., Hu, W., & Li, J. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107816 · Cited by 25
Rapamycin induces pluripotent genes associated with avoidance of replicative senescence
Pospelova, T. V., Bykova, T. V., Zubova, S. G., Katolikova, N. V., Yartzeva, N. M., & Pospelov, V. A. (2013) · Cell Cycle · doi:10.4161/cc.27396 · Cited by 26
“Agents and conditions that inhibit mTOR pathways all decelerate geroconversion.(21,30,36-45) Cell cycle arrest and geroconversion can be dissociated.”
BackgroundKlose, K., Packeiser, E., Müller, P., Granados-Soler, J. L., Schille, J. T., Goericke‐Pesch, S., Kietzmann, M., Escobar, H. M., & Nolte, I. J. A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0257403 · Cited by 24
Keizman, D., Ish‐Shalom, M., Sella, A., Gottfried, M., Maimon, N., Peer, A., Hammers, H. J., Eisenberger, M. A., Sinibaldi, V. J., Neiman, V., et al. (2016) · Clinical Genitourinary Cancer · doi:10.1016/j.clgc.2016.04.012 · Cited by 24
Muhammad, I. F., Borné, Y., Bao, X., Melander, O., Orho‐Melander, M., Nilsson, P. M., Nilsson, J. Å., & Engström, G. (2019) · Diabetes Care · doi:10.2337/dc18-2556 · Cited by 24
“The drug metformin has been shown to downregulate HER2 expression (36).”
BackgroundBazmandegan, G., Zamanian, M. Y., Giménez‐Llort, L., Nikbakhtzadeh, M., Kamiab, Z., & Heidari, M. (2022) · Current Molecular Pharmacology · doi:10.2174/1874467215666220620143655 · Cited by 24
Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP-activated Protein Kinase
Yi, Y., Gao, L., Wu, M. C., Ao, J., Zhang, C., Wang, X., Lin, M. T., Bergholz, J. S., Zhang, Y., & Xiao, Z. J. (2017) · Journal of Cancer · doi:10.7150/jca.19873 · Cited by 23
“At the molecular level, metformin modulates various key proteins, including mTOR, p53 and SIRT 1 [16], as well as down-regulation of Her2 and cyclin D1 expression [17, 18].”
BackgroundO’Neill, E. J., Moore, J., Song, J. S., & Tsiani, E. (2021) · Life · doi:10.3390/life12010052 · Cited by 22
“Activating AMPK using metformin, a mitochondrial complex I inhibitor, may be able to overcome breast cancer resistance to HER2 inhibitors while decreasing the risk of cardiotoxicity [16].”
BackgroundBroadhurst, P. J., & Hart, A. R. (2018) · Digestive Diseases and Sciences · doi:10.1007/s10620-018-5233-y · Cited by 21
Zhang, J., Jiao, K., Liu, J., & Xia, Y. (2018) · Oncology Letters · doi:10.3892/ol.2018.9382 · Cited by 23
“The mechanism may include the activation of the adenosine 5'monophosphate-activated protein kinase (AMPK) pathway (30,31), which reduces the proliferation of tumor cells by inhibiting epidermal growth factor receptor and insulin-like growth factor 1 receptor pathways (26,32,33).”
Memon, A. A., Bennet, L., Zöller, B., Wang, X., Palmér, K., Sundquist, K., & Sundquist, J. (2014) · Journal of Diabetes · doi:10.1111/1753-0407.12184 · Cited by 20
“Recent studies have demonstrated a protective role for the antidiabetic drug metformin against cancer(18) and studies in in vitro models have shown that metformin downregulates HER2.(7) The full-length HER2 receptor undergoes proteolytic cleavage, which results in the release of the soluble (circulating) extracellular…”
BackgroundChen, T.-W., Liang, Y., Feng, D., Lin-yu, T., Qi, K., Zhang, H.-Y., Wang, H.-X., Lin, Q.-S., & Kong, H. (2013) · PubMed · Cited by 20
Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo
Chen, Y., Wu, J.-X., Yang, S., Chen, M., Chen, T.-H., & Hsiao, Y.-H. (2021) · Cancers · doi:10.3390/cancers13184612 · Cited by 19
Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells
Rice, S., Pellatt, L. J., AHMETAGA, A., Bano, G., Mason, H. D., & Whitehead, S. A. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2108 · Cited by 19
Therapeutic effects of metformin in breast cancer: involvement of the immune system?
Schott, S., Bierhaus, A., Schütz, F., Beckhove, P., Schneeweiß, A., Sohn, C., & Domschke, C. (2011) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-011-1062-y · Cited by 19
Targeting Cancer Stem Cells with Defined Compounds and Drugs
Naujokat, C., & Laufer, S. (2013) · Journal of cancer research updates · Cited by 19
Diabetes and cancer: Debating the link through Ca2+/cAMP signalling
Bergantin, L. B. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.02.017 · Cited by 20
Metformin exposure and survival in head and neck cancer: A large population-based cohort study
Alcusky, M. J., Keith, S. W., Karagiannis, T., Rabinowitz, C., Louis, D. Z., & Maio, V. (2019) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12820 · Cited by 19
Avcı, O., Özdemir, E., Taşkıran, A. Ş., İnan, Z. D. Ş., & Gürsoy, S. (2022) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-022-02283-7 · Cited by 19
“Metformin is used in the clinic to lower blood sugar in patients with type 2 diabetes and has anti-inflammatory, anti-cancer and antioxidant properties (Vazquez-Martin et al. 2009).”
BackgroundShirooie, S., Sahebgharani, M., Esmaeili, J., & Dehpour, A. R. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27125 · Cited by 17
Efficacy of metformin in mediating cellular uptake and inducing apoptosis activity of doxorubicin
Shafa, M. H., Jalal, R., Kosari, N., & Rahmani, F. (2018) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2018.09.023 · Cited by 17
Alkhatib, Y., Rahman, Z. A., & Kuriakose, P. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2016.1239822 · Cited by 18
Metformin and long non-coding RNAs in breast cancer
Gholami, M., Klashami, Z. N., Ebrahimi, P., Mahboobipour, A. A., Farid, A. S., Vahidi, A., Zoughi, M., Asadi, M., & Amoli, M. M. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-03909-x · Cited by 21
Cao, X., Wu, Y., Wang, J., Liu, K., & Wang, X. (2017) · JNCI Cancer Spectrum · doi:10.1093/jncics/pkx007 · Cited by 17
Lee, D.-J., Kim, B., Lee, J. H., Park, S. J., Hong, S. P., Cheon, J. H., Kim, T. I., & Kim, W. H. (2012) · Korean Journal of Gastroenterology · doi:10.4166/kjg.2012.60.6.355 · Cited by 17
“또한 metformin은 insulin-like growth factor-1을 감소시키고 human epidermal growth factor receptor-2 신호를 억제함으로써 혈관 신생억제, 세포고사, 세포주기 정지 등을 유도하여 암을 억제 하기도 한다.(28-33) 최근 실험실 연구에서 metformin을 항암제”
From man to mouse and back again: advances in defining tumor AKTivities in vivo
Restuccia, D. F., & Hemmings, B. A. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.004671 · Cited by 16
“The AMPK activator metformin is well tolerated as an insulin-sensitizing agent and has also been shown to increase latency and reduce tumors in a mouse ErbB2 mammary model (Anisimov et al., 2005), possibly by inhibiting S6K1 activity and decreasing ErbB2 expression (Vazquez-Martin et al., 2009).”
BackgroundSerum HER-2 concentration is associated with insulin resistance and decreases after weight loss
Fernández‐Real, J. M., Menéndez, J. A., Frühbeck, G., Moreno‐Navarrete, J. M., Vázquez‐Martín, A., & Ricart, W. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-14 · Cited by 16
“Metformin led to down-regulation of HER-2 in in vitro models [27], and overexpression of fatty acid synthase gene (implicated in the synthesis of endogenous fatty acids and triglycerides) activated HER1/HER2 tyrosine kinase receptors in human breast epithelial cells [35].”
BackgroundSelf-citationExploiting p53 Status to Enhance Effectiveness of Chemotherapy by Lowering Associated Toxicity
Steelman, L. S., Martelli, A. M., Nicoletti, F., & McCubrey, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.247 · Cited by 16
Mousavi, S. E., Bagheri, A., Benisi-Kohansal, S., Azadbakht, L., & Esmaillzadeh, A. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.744500 · Cited by 15
“Earlier studies have also indicated that metformin is inversely related to this subtype of breast cancer, so that metformin can suppress overexpression of Her2 receptors and prevent breast cancer (62, 65, 66).”
BackgroundKim, D., Ahn, B., Kim, Y. S., Hur, D. Y., Yang, J. W., Park, G. B., Jang, J. E., Lee, E. J., Kwon, M. J., Kim, T. N., et al. (2019) · Journal of Diabetes Research · doi:10.1155/2019/2376512 · Cited by 15
“Metformin is a biguanide commonly administered to patients with type 2 diabetes mellitus to reduce blood glucose levels and protect against cancer by inducing cancer cell apoptosis [55, 56].”
BackgroundMetformine et cancer : de nouvelles perspectives pour un ancien médicament
Loubière, C., Dirat, B., Tanti, J., & Bost, F. (2013) · Annales d Endocrinologie · doi:10.1016/j.ando.2013.02.002 · Cited by 15
Metformin and sex: why suppression of aging may be harmful to young male mice
Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100264 · Cited by 13
“First, metformin via several mechanisms inhibits the mTOR pathway [9-15].”
BackgroundThe Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme
Sanati, M., Aminyavari, S., Mollazadeh, H., Motamed‐Sanaye, A., Bibak, B., Mohtashami, E., Teng, Y., Afshari, A. R., & Sahebkar, A. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220707103525 · Cited by 13
Metabolic Syndrome and Breast Cancer Risk: Is There a Role for Metformin?
Ibarra-Drendall, C., Dietze, E. C., & Seewaldt, V. L. (2011) · Current Breast Cancer Reports · doi:10.1007/s12609-011-0050-8 · Cited by 13
Repurposing Drugs in Small Animal Oncology
Giuliano, A., Horta, R. D. S., Vieira, R. A. D. M., Hume, K. R., & Dobson, J. M. (2022) · Animals · doi:10.3390/ani13010139 · Cited by 14
“In human breast carcinoma cells, metformin was able to decrease the level of epidermal growth factor 2 (HER-2), through the inhibition of protein synthesis (mediated by the m-TOR pathway) [63].”
BackgroundBilen, M. A., Lin, S.-H., Tang, D. G., Parikh, K., Lee, M.-H., Yeung, S. J., & Tu, S. (2015) · Case Reports in Oncological Medicine · doi:10.1155/2015/471861 · Cited by 12
Edwards, D. R. V., Hartmann, K. E., Wellons, M., et al. (2017) · BMC Women s Health · doi:10.1186/s12905-017-0386-y · Cited by 12
Obesity, Type-2 Diabetes and Cancer: Mechanistic Insights
Kashfi, K., Rosen, C. L., & Aslan, M. (2019) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2019032959 · Cited by 12
Evaluation of the effects of metformin administration on morphine tolerance in mice
Shirooie, S., Esmaeili, J., Sureda, A., et al. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134638 · Cited by 12
A case of liver hemangioma with markedly reduced tumor size after metformin treatment: a case report
Ōno, M., Sawada, K., & Okumura, T. (2016) · Clinical Journal of Gastroenterology · doi:10.1007/s12328-016-0705-0 · Cited by 11
“[21, 22]; decreased expression of the oncoprotein (human epidermal growth factor receptor type2) via direct and 5’ AMP-activated protein kinase (AMPK)-independent inhibition of p70S6K1 activity [23]; cell-cycle arrest induced via a decrease in cyclin D1 protein expression [24, 25]; promotion of cell death through acti…”
BackgroundMcFarlane, S. (2018) · Global Journal of Obesity Diabetes and Metabolic Syndrome · doi:10.17352/2455-8583.000032 · Cited by 10
“In breast cancer cells, metformin decreased levels of epidermal growth factor receptor 2 (HER2) through inhibition of the mTOR effector, p70S6K, a molecule responsible for phosphorylation of S6 ribosomal protein and thereby, protein synthesis [57].”
BackgroundMetformin for the Prevention of Bladder Cancer Recurrence: Is it Effective?
Heidari, F., Zade, S. A., Hosseini, S. H. M., & Ghadian, A. (2016) · Nephro-Urology Monthly · doi:10.5812/numonthly.30261 · Cited by 10
“Metformin has also been shown to decrease the activity and expression of HER2 in cancer cells, which is dose dependent and can be seen in higher administered doses of metformin (29-31).”
BackgroundBarakat, H. E., Hussein, R. R. S., Elberry, A. A., Zaki, M. A., & Ramadan, M. E. (2022) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2022.2051482 · Cited by 10
Angelis, V., Johnston, S. R. D., Ardestani, A. D., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.830097 · Cited by 9
“A large population-based cohort study correlates high levels of HER2 significantly with a higher risk of diabetes (8), and improvement of insulin sensitivity by metformin not only masters glycemia, but also downregulates HER2 expression (9).”
BackgroundRecent progress in targeting cancer
Demidenko, Z. N., & McCubrey, J. A. (2011) · Aging · doi:10.18632/aging.100421 · Cited by 8
“One of them is metformin, an anti-diabetic drug [171-186].”
BackgroundAbdel-Rahman, O. M. (2018) · Clinical Genitourinary Cancer · doi:10.1016/j.clgc.2018.09.016 · Cited by 8
Khan, H. J., Rohondia, S. O., Ahmed, Z. S. O., Zalavadiya, N., & Dou, Q. P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819668-7.00005-1 · Cited by 8
Damjanović, A., Matić, I. Z., Ðorđić, M., et al. (2014) · Pathology & Oncology Research · doi:10.1007/s12253-014-9864-9 · Cited by 7
“Apparently, it seems that results of our study are different from recently published data, but experiments in these publications were observed at higher metformin concentrations [24, 25].”
ResultMetformin as a Novel Component of Metronomic Chemotherapeutic Use: A Hypothesis
Duque, J. E., Vélez, J., Samudio, I. J., & Lai, E. (2012) · Journal of Experimental & Clinical Medicine · doi:10.1016/j.jecm.2012.04.002 · Cited by 7
Advantages, Challenges, and Impact of Drug Repurposing for Cancer Treatment
Zafar, R., Safdar, I., Munir, A., Zahid, M. R., & Serfraz, S. (2025) · Pharmaceutical science. · doi:10.5772/intechopen.1008768 · Cited by 5
Huang, Y. H., Han, X., Chang, T., Li, F.-F., Chen, X., & She, Y. (2022) · Scientific Reports · doi:10.1038/s41598-022-07549-x · Cited by 6
Kim, J.-S., Kim, M. Y., & Hong, S. (2023) · Cancers · doi:10.3390/cancers15194768 · Cited by 8
“…with improved survival in patients with different types of cancers, including those with GC after gastrectomy [16], those with diabetes who were diagnosed with GC in a Swedish population-based cohort study [17], those with HER2 positive BC in a population study [18], and laboratory studies [19–21].”
BackgroundKnowledge mapping of metformin use on cancers: a bibliometric analysis (2013–2023)
Pan, C., Wei, Y., Dai, J., Yang, L., Ding, Z., & Wang, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1388253 · Cited by 5
de Assis, E. B. T., Ferreira, M. Y., de Oliveira, J. S., Mitre, L. P., Corrêa, E. M., Coelho, L. L. S., Moreno, D. A., & Polverini, A. D. (2025) · World Neurosurgery · doi:10.1016/j.wneu.2025.123842 · Cited by 6
Viollet, B., & Foretz, M. (2011) · Médecine des Maladies Métaboliques · doi:10.1016/s1957-2557(11)70183-3 · Cited by 5
Pharmacological Approaches to Improve Ageing
Pedro, J., Camello‐Almaraz, C., & Maria, J. (2012) · InTech eBooks · doi:10.5772/33389 · Cited by 4
“, 2005) and to suppress S6K1 activity in cultured proliferating epithelial cells (Vazquez-Martin et al., 2009).”
Role of insulin sensitising agents in altering PSA level in PCOS
Panigrahy, R., Singh, B., Pattnaik, T., et al. (2017) · International Journal of Reproduction Contraception Obstetrics and Gynecology · doi:10.18203/2320-1770.ijrcog20175013 · Cited by 4
“Mechanisms which underlie the effects of metformin on PSA level in those patients are mostly attributable to its anti neoplastic action.(12,13)”
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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