Melloni Mattia, Sergi Domenico, Passaro Angelina, Neri Luca Maria
Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
Laboratory for Technologies of Advanced Therapies (LTTA)-Electron Microscopy Center, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
Int J Mol Sci. 2025 Aug 4;26(15):7523. doi: 10.3390/ijms26157523.
Breast cancer (BC) progression appears to be significantly influenced by the diabetic microenvironment, characterised by hyperglycaemia and hyperinsulinemia, though the exact cellular mechanisms remain partly unclear. This study investigated the effects of exposure to supra-physiological levels of glucose and insulin on two distinct BC cell models: hormone-responsive MCF-7 cells and triple-negative MDA-MB-231 cells. To evaluate the effects triggered by high insulin level in different BC cell subtypes, we analysed the activation status of PI3K/AKT and MAPK pathways, cell proliferation, cell distribution in cell cycle phases and cell migration. High insulin level significantly activates the insulin metabolic pathway via AKT phosphorylation in both cell lines while inducing pro-proliferative stimulus and modulation of cell distribution in cell cycle phases only in the hormone-responsive MCF-7 cell line. On the contrary, high-glucose containing medium alone did not modulate proliferation nor further increased it when combined with high insulin level in both the investigated cell lines. However, following insulin treatment, the MAPK pathway remained unaffected, suggesting that the proliferation effects in the MCF-7 cell line are mediated by AKT activation. This linkage was also demonstrated by AKT phosphorylation blockade, driven by the AKT inhibitor MK-2206, which negated the proliferative stimulus. Interestingly, while MDA-MB-231 cells, following chronic hyperinsulinemia exposure, did not exhibit enhanced proliferation, they displayed a marked increase in migratory behaviour. These findings suggest that chronic hyperinsulinemia, but not hyperglycaemia, exerts subtype-specific effects in BC, highlighting the potential of targeting insulin pathways for therapeutic intervention.
乳腺癌（BC）的进展似乎受到以高血糖和高胰岛素血症为特征的糖尿病微环境的显著影响，尽管确切的细胞机制仍部分不明。本研究调查了暴露于超生理水平的葡萄糖和胰岛素对两种不同的BC细胞模型的影响：激素反应性MCF-7细胞和三阴性MDA-MB-231细胞。为了评估高胰岛素水平在不同BC细胞亚型中引发的影响，我们分析了PI3K/AKT和MAPK信号通路的激活状态、细胞增殖、细胞周期各阶段的细胞分布以及细胞迁移。高胰岛素水平通过AKT磷酸化在两种细胞系中均显著激活胰岛素代谢通路，同时仅在激素反应性MCF-7细胞系中诱导促增殖刺激并调节细胞周期各阶段的细胞分布。相反，单独的高糖培养基在两种被研究的细胞系中既不调节增殖，与高胰岛素水平联合时也不会进一步增加增殖。然而，胰岛素处理后，MAPK信号通路未受影响，这表明MCF-7细胞系中的增殖效应是由AKT激活介导的。AKT抑制剂MK-2206驱动的AKT磷酸化阻断也证明了这种联系，它消除了增殖刺激。有趣的是，虽然MDA-MB-231细胞在慢性高胰岛素血症暴露后未表现出增殖增强，但它们的迁移行为却显著增加。这些发现表明，慢性高胰岛素血症而非高血糖在BC中发挥亚型特异性作用，突出了靶向胰岛素信号通路进行治疗干预的潜力。
