Metformin in breast cancer - an evolving mystery

Laura Camacho, Atreyi Dasgupta, Sao Jiralerspong, Laura Camacho, Atreyi Dasgupta, Sao Jiralerspong

Abstract

Metformin, a diabetes drug with well-established side effect and safety profiles, has been widely studied for its anti-tumor activities in a number of cancers, including breast cancer. But its mechanism of action in the clinical arena remains elusive. In a window of opportunity trial of metformin in non-diabetic breast cancer patients, Dowling and colleagues examined both the direct actions of the drug on cancer cells (as mediated by AMP kinase), as well as its indirect actions (as mediated by circulating insulin). The data suggest that short-term administration of metformin in this setting has anti-tumor effects significantly involving the indirect, insulin-dependent pathway. The role of the direct pathway remains to be determined. This study represents an important step forward in establishing one of several possible mechanisms for metformin, information that will be useful in determining candidate biomarkers to evaluate in large clinical trials of metformin, such as the ongoing NCIC CTG MA.32 trial of adjuvant metformin. The potential significance of these data for metformin in the treatment of breast cancer is discussed here.

References

    1. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer. 2008;8:501–5. doi: 10.3816/CBC.2008.n.060.
    1. Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat. 2011;128:783–94. doi: 10.1007/s10549-011-1612-1.
    1. Hadad SM, Coates P, Jordan LB, Dowling RJ, Chang MC, Done SJ, et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat. 2015;150:149–55. doi: 10.1007/s10549-015-3307-5.
    1. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30:2593–600. doi: 10.1200/JCO.2011.39.3769.
    1. Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, et al. The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer. 2013;109:2792–7. doi: 10.1038/bjc.2013.657.
    1. DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat. 2014;148:81–90. doi: 10.1007/s10549-014-3141-1.
    1. Kalinsky K, Crew KD, Refice S, Xiao T, Wang A, Feldman SM, et al. Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer. Cancer Invest. 2014;32:150–7. doi: 10.3109/07357907.2014.889706.
    1. Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015;107:djv006. doi: 10.1093/jnci/djv006.
    1. Niraula S, Dowling RJ, Ennis M, Chang MC, Done SJ, Hood N, et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat. 2012;135:821–30. doi: 10.1007/s10549-012-2223-1.
    1. Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR, et al. Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res. 2015;17:32. doi: 10.1186/s13058-015-0540-0.
    1. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28. doi: 10.1038/nrc2536.
    1. Zhu P, Davis M, Blackwelder AJ, Bachman N, Liu B, Edgerton S, et al. Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev Res (Phila) 2014;7:199–210. doi: 10.1158/1940-6207.CAPR-13-0181.
    1. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, Thor AD. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8:909–15. doi: 10.4161/cc.8.6.7933.
    1. Schuler KM, Rambally BS, DiFurio MJ, Sampey BP, Gehrig PA, Makowski L, Bae-Jump VL. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. 2015;4:161–73. doi: 10.1002/cam4.353.
    1. Hardie DG, Alessi DR. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biol. 2013;11:36. doi: 10.1186/1741-7007-11-36.

Source: PubMed

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