Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Breast Cancer Res. 2011 May 19;13(3):R52. doi: 10.1186/bcr2883.
Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth factor receptor and human epidermal growth factor receptor 2. Yet, the direct role of IGF-1R signaling itself in antiestrogen resistance remains obscure. In the present study, we sought to elucidate whether antiestrogen resistance is induced directly by IGF-1R signaling in response to its ligand IGF-1 stimulation.
A breast cancer cell line ectopically expressing human wild-type IGF-1R, MCF7/IGF-1R, was established by retroviral transduction and colony selection. Cellular antiestrogen sensitivity was evaluated under estrogen-depleted two-dimensional (2D) and 3D culture conditions. Functional activities of the key IGF-1R signaling components in antiestrogen resistance were assessed by specific kinase inhibitor compounds and small interfering RNA.
Ectopic expression of IGF-1R in ER-positive MCF7 human breast cancer cells enhanced IGF-1R tyrosine kinase signaling in response to IGF-1 ligand stimulation. The elevated IGF-1R signaling rendered MCF7/IGF-1R cells highly resistant to the antiestrogens tamoxifen and fulvestrant. This antiestrogen-resistant phenotype involved mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B pathways downstream of the IGF-1R signaling hub and was independent of ER signaling. Intriguingly, a MAPK/ERK-dependent agonistic behavior of tamoxifen at low doses was triggered in the presence of IGF-1, showing a mild promitogenic effect and increasing ER transcriptional activity.
Our data provide evidence that the IGF-1/IGF-1R signaling axis may play a causal role in antiestrogen resistance of breast cancer cells, despite continuous suppression of ER transcriptional function by antiestrogens.
胰岛素样生长因子 1（IGF-1）受体（IGF-1R）在所有乳腺癌亚型中均发生磷酸化。过去的研究结果表明，IGF-1R 通过与雌激素受体（ER）信号的交叉对话以及通过其在表皮生长因子受体和人表皮生长因子受体 2 上游的作用来介导抗雌激素耐药。然而，IGF-1R 信号本身在抗雌激素耐药中的直接作用仍然不清楚。在本研究中，我们试图阐明 IGF-1R 信号是否通过其配体 IGF-1 刺激直接诱导抗雌激素耐药。
通过逆转录病毒转导和集落选择，建立了乳腺癌细胞系 MCF7/IGF-1R 过表达人野生型 IGF-1R。在雌激素耗竭的二维（2D）和 3D 培养条件下评估细胞抗雌激素敏感性。通过特异性激酶抑制剂化合物和小干扰 RNA 评估关键 IGF-1R 信号成分在抗雌激素耐药中的功能活性。
IGF-1R 在 ER 阳性 MCF7 人乳腺癌细胞中的过表达增强了 IGF-1R 酪氨酸激酶信号对 IGF-1 配体刺激的反应。升高的 IGF-1R 信号使 MCF7/IGF-1R 细胞对他莫昔芬和氟维司群等抗雌激素药物高度耐药。这种抗雌激素耐药表型涉及 IGF-1R 信号枢纽下游的丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）和磷脂酰肌醇 3-激酶/蛋白激酶 B 途径，并且独立于 ER 信号。有趣的是，在 IGF-1 存在的情况下，低剂量的他莫昔芬触发了 MAPK/ERK 依赖性激动作用，表现出轻微的促有丝分裂作用，并增加了 ER 转录活性。
我们的数据提供了证据表明，尽管抗雌激素药物持续抑制 ER 转录功能，但 IGF-1/IGF-1R 信号轴可能在乳腺癌细胞的抗雌激素耐药中起因果作用。
