Northern Institute for Cancer Research, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, UK.
Neoplasia. 2011 Jun;13(6):504-15. doi: 10.1593/neo.101590.
Triple-negative breast cancers have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The prevailing view is that targeting the insulin-like growth factor (IGF) signal transduction pathway will not be beneficial for triple-negative breast cancers because their growth is not IGF-responsive. The present study investigates the importance of IGFs in the proliferation and survival of triple-negative breast cancer cells. Estrogen and progesterone receptors, HER2, type I IGF, and insulin receptors were measured by Western transfer analysis. The effects of IGF-1 on proliferation were assessed by DNA quantitation and on cell survival by poly (ADP-ribose) polymerase cleavage. The effect of IGF-1 on phosphorylation of the IGF receptors, Akt and mitogen-activated protein kinase, was measured by Western transfer analysis. Seven cell lines were identified as models of triple-negative breast cancer and shown to express IGF receptors at levels similar to those present in estrogen-responsive cell lines known to respond to IGFs. IGF-1 increased the proliferation and cell survival of all triple-negative cell lines. Proliferation was attenuated after reduction of type I IGF receptor expression. Cells that express higher levels of receptor were more sensitive to subnanomolar IGF-1 concentrations, but the magnitude of the effects was not correlated simply with the absolute amount or phosphorylation of the IGF receptors, Akt or mitogen-activated protein kinase. These results show that IGFs stimulate cell proliferation and promote cell survival in triple-negative breast cancer cells and warrant investigation of the IGF signal transduction pathway as a therapeutic target for the treatment of triple-negative breast cancer.
三阴性乳腺癌预后不良，不能进行内分泌或 HER2 靶向治疗。目前的观点认为，针对胰岛素样生长因子 (IGF) 信号转导通路不会对三阴性乳腺癌有益，因为它们的生长不受 IGF 影响。本研究探讨了 IGF 在三阴性乳腺癌细胞增殖和存活中的重要性。采用 Western 转移分析测定雌激素和孕激素受体、HER2、I 型 IGF 和胰岛素受体。通过 DNA 定量评估 IGF-1 对增殖的影响，通过多聚（ADP-核糖）聚合酶切割评估对细胞存活的影响。通过 Western 转移分析测定 IGF-1 对 IGF 受体、Akt 和丝裂原活化蛋白激酶磷酸化的影响。确定了 7 种细胞系作为三阴性乳腺癌模型，并证明它们表达 IGF 受体的水平与已知对 IGF 有反应的雌激素反应性细胞系中的 IGF 受体表达水平相似。IGF-1 增加了所有三阴性细胞系的增殖和细胞存活。降低 I 型 IGF 受体表达后，增殖受到抑制。表达更高受体水平的细胞对亚纳摩尔浓度的 IGF-1 更敏感，但效应的幅度与 IGF 受体、Akt 或丝裂原活化蛋白激酶的绝对数量或磷酸化无关。这些结果表明，IGF 刺激三阴性乳腺癌细胞的增殖并促进其存活，这证明 IGF 信号转导通路是治疗三阴性乳腺癌的治疗靶点。
