Department of Medicine, Division of Clinical Epidemiology at the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Princess Margaret Hospital, University of Toronto; Mount Sinai Hospital, 1284-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Breast. 2011 Oct;20 Suppl 3:S31-5. doi: 10.1016/S0960-9776(11)70291-0.
Obesity and insulin resistance have been associated with breast cancer risk, and breast cancer outcomes. Recent research has focused on insulin as a potential biologic mediator of these effects given frequent expression of insulin/IGF-1 receptors on breast cancer cells which, when activated, can stimulate signaling through PI3K and Ras-Raf signaling pathways to enhance proliferation. Metformin, a commonly used diabetes drug, lowers insulin in non-breast diabetic cancer patients, likely by reducing hepatic gluconeogenesis; it also appears to have potential insulin independent direct effects on tumor cells which are mediated by activation of AMPK with downstream inhibition of mTOR. There is growing epidemiologic, clinical and preclinical (in vitro and in vivo) evidence in keeping with anticancer effects of metformin in breast and other cancers. This has led to the hypothesis that metformin may be effective in breast cancer prevention and treatment. Clinical studies in the neoadjuvant and adjuvant settings are ongoing; additional Phase 2 trials in the metastatic setting and proof of principle studies in the prevention setting are planned.
肥胖和胰岛素抵抗与乳腺癌风险和乳腺癌结局相关。鉴于乳腺癌细胞经常表达胰岛素/IGF-1 受体，这些受体被激活后可以通过 PI3K 和 Ras-Raf 信号通路刺激信号转导，从而增强增殖，因此最近的研究集中在胰岛素作为这些作用的潜在生物学介导物上。二甲双胍是一种常用的糖尿病药物，可降低非乳腺癌糖尿病患者的胰岛素水平，可能是通过减少肝糖异生来实现的；它似乎还具有通过激活 AMPK 对肿瘤细胞的潜在胰岛素非依赖性直接作用，从而下游抑制 mTOR。越来越多的流行病学、临床前和临床（体外和体内）证据表明，二甲双胍对乳腺癌和其他癌症具有抗癌作用。这导致了二甲双胍可能在乳腺癌预防和治疗中有效的假说。新辅助和辅助治疗中的临床研究正在进行中；计划在转移性疾病中进行更多的 2 期试验，并在预防环境中进行原理验证研究。
