PDF(Pubmed)
Abstract：
Metformin shows promise in breast cancer prevention, but its underlying mechanisms remain unclear. This study investigated the impact of metformin on the repopulation dynamics of mammary epithelial cells (MECs) and the signaling pathways in non-tumorigenic FVB/N mice. This study aimed to enhance our understanding of the role of metformin in reducing the susceptibility of MECs in premalignant tissues to oncogenic factors. In this study, female mice were administered 200 mg/kg/day of metformin via intraperitoneal (i.p.) injection from 8 to 18 weeks of age. After this treatment period, morphogenesis, flow cytometry, analyses of MEC stemness, and RNA sequencing were performed. The study findings indicated that metformin treatment in adult mice reduced mammary gland proliferation, as demonstrated by decreased Ki67+ cells and lateral bud formation. Additionally, metformin significantly reduced both basal and mammary repopulating unit subpopulations, indicating an impact on mammary epithelial cell repopulation. Mammosphere, colony-forming cell, and 3D culture assays revealed that metformin adversely affected mammary epithelial cell stemness. Furthermore, metformin downregulated signaling in key pathways including AMPK/mTOR, MAPK/Erk, PI3K/Akt, and ER, which contribute to its inhibitory effects on mammary proliferation and stemness. Transcriptome analysis with RNA sequencing indicated that metformin induced significant downregulation of genes involved in multiple critical pathways. KEGG-based pathway analysis indicated that genes in PI3K/Akt, focal adhesion, ECM-receptor, small cell lung cancer and immune-modulation pathways were among the top groups of differentially regulated genes. In summary, our research demonstrates that metformin inhibits MEC proliferation and stemness, accompanied by the downregulation of intrinsic signaling. These insights suggest that the regulatory effects of metformin on premalignant mammary tissues could potentially delay or prevent the onset of breast cancer, offering a promising avenue for developing new preventive strategies.
摘要：
二甲双胍在预防乳腺癌方面显示出希望，但其潜在机制仍不清楚。这项研究调查了二甲双胍对非致瘤FVB/N小鼠乳腺上皮细胞（MEC）的再种群动力学和信号通路的影响。这项研究旨在增强我们对二甲双胍在降低癌前组织中MECs对致癌因子的敏感性中的作用的理解。在这项研究中,雌性小鼠从8至18周龄通过腹膜内(i.p.)注射给予200mg/kg/天的二甲双胍。经过这个治疗期,形态发生,流式细胞术,MEC干性分析，并进行RNA测序。研究结果表明，二甲双胍治疗成年小鼠减少乳腺增生，如Ki67细胞减少和侧芽形成所证明的。此外,二甲双胍显著减少基础和乳腺再种群单位亚群，表明对乳腺上皮细胞再增殖的影响。乳球，集落形成细胞,和3D培养分析显示，二甲双胍对乳腺上皮细胞干性产生不利影响。此外，二甲双胍下调关键通路中的信号传导，包括AMPK/mTOR，MAPK/Erk,PI3K/Akt,ER,这有助于其对乳腺增殖和干性的抑制作用。RNA测序的转录组分析表明，二甲双胍诱导参与多个关键途径的基因显著下调。基于KEGG的通路分析表明，PI3K/Akt中的基因，病灶粘连,ECM受体，小细胞肺癌和免疫调节通路是差异调节基因的前几组.总之,我们的研究表明，二甲双胍抑制MEC增殖和干性，伴随着内在信号的下调。这些见解表明，二甲双胍对癌前乳腺组织的调节作用可能会延迟或预防乳腺癌的发作。为开发新的预防策略提供了一个有希望的途径。
