Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial
Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial
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DOI：
10.1007/s10549-015-3307-5
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发表时间：
2015-02-01
影响因子：
3.8
通讯作者：
Thompson, Alastair M.
中科院分区：
文献类型：
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作者：
Hadad, Sirwan M.;Coates, Philip;Thompson, Alastair M.
二甲双胍对乳腺癌具有治疗潜力，但体内作用机制仍不确定。本研究在术前机会窗试验中检查了二甲双胍在原发性乳腺癌中的生物标志物作用。患有可手术浸润性乳腺癌的非糖尿病女性随机接受开放标签的术前二甲双胍（500 mg每日一次，持续1周，然后1 g每日两次，持续另一周）或作为对照，不接受二甲双胍。两组患者均在随机化前和手术时进行了组织芯活检。在福尔马林固定的石蜡包埋核心上进行磷酸化AMPK（pAMPK）、磷酸化Akt（pAkt）、胰岛素受体、裂解的半胱天冬酶-3和Ki 67的免疫组织化学，对治疗设盲评分，并通过配对t检验进行分析。在二甲双胍治疗的患者中，与对照组相比，证实了pAMPK的显著上调（配对t检验，p = 0.04）和pAkt的显著下调（配对t检验，p = 0.043）。二甲双胍治疗后，胰岛素受体和血清胰岛素保持相似，而对照组胰岛素受体和胰岛素升高。在二甲双胍治疗的患者中观察到Ki 67和裂解的半胱天冬酶-3的显著福尔斯下降（配对t检验，p = 0.044），但在对照组中未观察到。变化与体重指数无关。这些生物标志物数据表明，二甲双胍在乳腺癌患者体内的作用机制是通过上调肿瘤pAMPK、下调pAkt和抑制胰岛素反应，反映细胞抑制机制而非细胞毒性机制。
Metformin has therapeutic potential against breast cancer, but the mechanisms of action in vivo remain uncertain. This study examined biomarker effects of metformin in primary breast cancer in a preoperative window of opportunity trial. Non-diabetic women with operable invasive breast cancer were randomized to receive open label pre-operative metformin (500 mg daily for 1 week then 1 g twice daily for a further week) or as controls, not receiving metformin. Patients in both arms had a core biopsy pre-randomisation and again at the time of surgery. Immunohistochemistry for phospho-AMPK (pAMPK), phospho-Akt (pAkt), insulin receptor, cleaved caspase-3, and Ki67 was performed on formalin-fixed paraffin-embedded cores, scored blinded to treatment and analysed by paired t test. In metformin-treated patients, significant up-regulation of pAMPK (paired t test, p = 0.04) and down-regulation of pAkt (paired t test, p = 0.043) were demonstrated compared to the control group. Insulin receptor and serum insulin remained similar following metformin treatment compared with a rise in insulin receptor and insulin in controls. Significant falls in Ki67 and cleaved caspase-3 (paired t test, p = 0.044) were seen in the metformin-treated patients but not in the control group. Changes were independent of body mass index. These biomarker data suggest mechanisms for metformin action in vivo in breast cancer patients via up-regulation of tumor pAMPK, down-regulation of pAkt, and suppression of insulin responses reflecting cytostatic rather than cytotoxic mechanisms.