Department of Pathology, University of Colorado Denver School of Medicine, Aurora, CO, USA.
Cell Cycle. 2011 Sep 1;10(17):2959-66. doi: 10.4161/cc.10.17.16359.
We have shown that erbB2 altered breast cancer cells are less sensitive to the anti-proliferative effects of metformin than triple negative cells, and have described the differences of molecular mechanisms of metformin action by tumor subtypes. We hypothesized that metformin may be more effective against trastuzumab-resistant erbB2-overexpressing breast cancer cells because it targets the critical signaling pathways that are altered with resistance. BT474, SKBR3 and derived trastuzumab-resistant sublines BT474-HR20 (HR20) and SKBR3-pool2 (pool2) were used to test this hypothesis. Metformin treatment resulted in significantly more inhibition of proliferation and clonogenicity in resistant sublines. It decreased erbB2/insulin-like growth factor-1 receptor (IGF-1R) complexes (present only in the resistant sublines) without altering erbB2 expression, and reduced the expression and activity of erbB3 and IGF-1R in the trastuzumab-resistant but not parental cells. Trastuzumab-resistant sublines were resistant to rapamycin induced changes in mTOR activity and cell growth. In contrast, both BT474 and HR20 cells were highly sensitive to inhibitors of Src (Dasatinib) and PI-3K (LY294002). The pool2 cells showed higher sensitivity than SKBR3 cells to LY294002, but not Dasatinib. On the basis of these data, metformin appears to be significantly more effective against trastuzumab-resistant as compared to sensitive breast cancer cells. Metformin disrupts erbB2/IGF-1R complexes, erbB3 and IGF-1R expression and activity, as well as Src kinase and/or PI-3K/Akt signaling. This action appears to be independent of mTOR signaling. Our findings provide a rationale to study the effects of metformin on patients with erbB2 positive tumors treated with trastuzumab, with or without resistance.
我们已经证明，与三阴性细胞相比，erbB2 改变的乳腺癌细胞对二甲双胍的抗增殖作用的敏感性较低，并且已经描述了肿瘤亚型的二甲双胍作用的分子机制的差异。我们假设二甲双胍可能对曲妥珠单抗耐药 erbB2 过表达的乳腺癌细胞更有效，因为它针对的是与耐药性改变的关键信号通路。使用 BT474、SKBR3 和衍生的曲妥珠单抗耐药亚系 BT474-HR20（HR20）和 SKBR3-pool2（pool2）来检验这一假设。二甲双胍处理导致耐药亚系的增殖和集落形成明显受到抑制。它降低了 erbB2/胰岛素样生长因子-1 受体（IGF-1R）复合物（仅存在于耐药亚系中），而不改变 erbB2 表达，并降低了 erbB3 和 IGF-1R 的表达和活性在曲妥珠单抗耐药但不是亲本细胞中。曲妥珠单抗耐药亚系对雷帕霉素诱导的 mTOR 活性和细胞生长变化具有抗性。相比之下，BT474 和 HR20 细胞对Src（Dasatinib）和 PI-3K（LY294002）抑制剂均高度敏感。与 SKBR3 细胞相比，pool2 细胞对 LY294002 更敏感，但对 Dasatinib 不敏感。基于这些数据，二甲双胍对曲妥珠单抗耐药的乳腺癌细胞比对敏感的乳腺癌细胞更有效。二甲双胍破坏 erbB2/IGF-1R 复合物、erbB3 和 IGF-1R 的表达和活性，以及 Src 激酶和/或 PI-3K/Akt 信号通路。这种作用似乎独立于 mTOR 信号通路。我们的研究结果为研究二甲双胍对曲妥珠单抗治疗的 erbB2 阳性肿瘤患者的影响提供了依据，无论是否存在耐药性。
