Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes.
Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes.
复制标题
DOI：
10.1186/bcr2883
复制
发表时间：
2011-05-19
期刊：
影响因子：
--
通讯作者：
van de Water B
中科院分区：
文献类型：
--
作者：
Zhang Y;Moerkens M;Ramaiahgari S;de Bont H;Price L;Meerman J;van de Water B
胰岛素样生长因子1（IGF-1）受体（IGF-1 R）在所有乳腺癌亚型中均被磷酸化。过去的研究结果表明，IGF-1 R通过与雌激素受体（ER）信号传导的串扰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上游的作用介导抗雌激素抵抗。然而，IGF-1 R信号本身在抗雌激素抵抗中的直接作用仍然不清楚。在本研究中，我们试图阐明抗雌激素抵抗是否直接诱导IGF-1 R信号响应其配体IGF-1刺激。通过逆转录病毒转导和集落筛选，建立了异位表达人野生型IGF-1 R的乳腺癌细胞系MCF 7/IGF-1 R。在雌激素耗尽的二维（2D）和3D培养条件下评价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评估抗雌激素抵抗中关键IGF-1 R信号传导组分的功能活性。ER阳性MCF 7人乳腺癌细胞中IGF-1 R的异位表达增强了IGF-1受体酪氨酸激酶信号对IGF-1配体刺激的响应。升高的IGF-1 R信号使MCF 7/IGF-1 R细胞对抗雌激素他莫昔芬和氟维司群高度耐药。这种抗雌激素耐药表型涉及IGF-1 R信号中枢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，并且不依赖于ER信号传导。有趣的是，在IGF-1的存在下，低剂量的他莫昔芬的MAPK/ERK依赖性激动行为被触发，显示出温和的促有丝分裂作用和增加的ER转录活性。我们的数据提供的证据表明，IGF-1/IGF-1 R信号轴可能在乳腺癌细胞的抗雌激素抵抗中发挥因果作用，尽管抗雌激素持续抑制ER转录功能。
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.
登录
查看更多内容
DOI：
10.1073/pnas.0810221106
发表时间：
2009-02-17
影响因子：
11.1
作者：
Klinakis, Apostolos;Szabolcs, Matthias;Efstratiadis, Argiris
通讯作者：
Efstratiadis, Argiris
影响因子：
11.5
作者：
Chitnis, Meenali M.;Yuen, John S. P.;Macaulay, Valentine M.
通讯作者：
Macaulay, Valentine M.
影响因子：
6.4
作者：
Ghayad, Sandra E.;Vendrell, Julie A.;Cohen, Pascale A.
通讯作者：
Cohen, Pascale A.
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP
影响因子：
2.5
作者：
Fagan, Dedra H.;Yee, Douglas
通讯作者：
Yee, Douglas