Obesity and type 2 diabetes mellitus (T2DM) associate with increased incidence and mortality from many cancers, including breast cancer. The mechanisms involved in this relation remain poorly understood. Our study aimed to investigate the in vitro effect of high levels of glucose, insulin, leptin, TNF-α, INF-γ and oxidative stress (induced with tert-butylhydroperoxide (TBH)), which are associated with T2DM, upon glucose uptake by breast cancer (MCF-7 and MDA-MB-231) and non-cancer (MCF-12A) cells and to correlate this effect with their effects upon cellular characteristics associated with cancer progression (cell proliferation, viability, migration, angiogenesis and apoptosis).

³H-DG uptake was markedly inhibited by a selective GLUT1 inhibitor (BAY-876) in all cell lines, proving that ³H-DG uptake is mainly GLUT1-mediated. TBH (2.5 μM), insulin (50 nM), leptin (500 ng/ml) and INF-y (100 ng/ml) stimulate GLUT1-mediated ³H-DG (1 mM) uptake by both ER-positive and triple-negative breast cancer cell lines. TBH and leptin, but not insulin and INF-γ, increase GLUT1 mRNA levels. Insulin and leptin (in both ER-positive and triple-negative breast cancer cell lines) and TBH (in the triple-negative cell line) have a proproliferative effect and leptin possesses a cytoprotective effect in both breast cancer cell lines that can contribute to cancer progression. The effects of TBH, insulin, leptin and INF-γ upon breast cancer cell proliferation and viability are GLUT1-dependent.

In conclusion, T2DM-associated characteristics induce changes in GLUT1-mediated glucose uptake that can contribute to cancer progression. Moreover, we conclude that BAY-876 can be a strong candidate for development of a new effective anticancer agent against breast cancer.

肥胖和2型糖尿病（T2DM）与许多癌症（包括乳腺癌）的发病率和死亡率增加相关。这种关系涉及的机制仍然知之甚少。我们的研究旨在研究高水平的葡萄糖，胰岛素，瘦素，TNF-α，INF-γ和氧化应激（由叔丁基氢过氧化物（TBH）诱导）的体外效应，这些氧化应激与T2DM相关，并被葡萄糖摄取。乳腺癌（MCF-7和MDA-MB-231）细胞和非癌细胞（MCF-12A）细胞，并将这种作用与其对与癌症进展相关的细胞特征（细胞增殖，生存力，迁移，血管生成和凋亡）的影响相关联。

在所有细胞系中，选择性GLUT1抑制剂（BAY-876）显着抑制³ H-DG的摄取，证明³ H-DG的摄取主要是GLUT1介导的。TBH（2.5μM），胰岛素（50 nM），瘦素（500 ng / ml）和INF-y（100 ng / ml）刺激GLUT1介导的³ER阳性和三阴性乳腺癌细胞系均摄取H-DG（1 mM）。TBH和瘦蛋白会增加GLUT1 mRNA水平，但不会增加胰岛素和INF-γ。胰岛素和瘦素（在ER阳性和三阴性乳腺癌细胞系中）和TBH（在三阴性细胞系中）具有促增殖作用，而瘦素在两种可能导致癌症的乳腺癌细胞系中均具有细胞保护作用进展。TBH，胰岛素，瘦素和INF-γ对乳腺癌细胞增殖和生存能力的影响取决于GLUT1。

总之，与T2DM相关的特征会诱导GLUT1介导的葡萄糖摄取发生变化，从而可能导致癌症进展。此外，我们得出的结论是，BAY-876可以成为开发新型有效的抗乳腺癌抗癌药的强有力候选者。