Strømland Pouda Panahandeh, Bertelsen Bjørn-Erik, Viste Kristin, Chatziioannou Anastasia Chrysovalantou, Bellerba Federica, Robinot Nivonirina, Trolat Amarine, Flågeng Marianne Hauglid, Scalbert Augustin, Keski-Rahkonen Pekka, Sears Dorothy D, Bonanni Bernardo, Gandini Sara, Johansson Harriet, Mellgren Gunnar
Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Sci Rep. 2025 May 15;15(1):16897. doi: 10.1038/s41598-025-01705-9.
Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1, MT-RNR2, EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors.Trial registration: MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.
二甲双胍可降低肥胖和2型糖尿病患者患乳腺癌的风险。然而，我们对二甲双胍对乳腺癌复发影响的了解有限。在随机双盲安慰剂对照的II期试验MetBreCS中，我们研究了体重指数（BMI）>25kg/m²的乳腺癌幸存者在接受二甲双胍治疗后乳腺组织的变化。为了确定二甲双胍调节的信号通路，我们使用双变量和功能分析整合了转录组学、代谢组学和类固醇激素谱。我们发现MS4A1、HBA2、MT-RNR1、MT-RNR2、EGFL6和FDCSP的表达在接受二甲双胍治疗的绝经后女性的乳腺组织中存在差异。转录组学和代谢组学谱的整合显示，在二甲双胍治疗组中，与精氨酸和瓜氨酸水平降低相关的免疫反应基因下调。转录组学和类固醇激素谱的整合表明，在接受二甲双胍治疗的绝经后女性的乳腺组织中，类固醇激素生物合成和代谢途径富集，CYP11A1和CYP1B1的表达高度负相关。我们的结果表明，接受二甲双胍治疗的绝经后乳腺癌幸存者的乳腺组织基因表达有特定变化，这可能会阻止新肿瘤的发生。试验注册：MetBreCs试验于2015年10月7日在欧盟临床试验注册中心（EudraCT协议编号：2015-001001-14）注册。
