The IGF Pathway Regulates ERα through a S6K1-Dependent Mechanism in Breast Cancer Cells
The IGF Pathway Regulates ERα through a S6K1-Dependent Mechanism in Breast Cancer Cells
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DOI：
10.1210/me.2010-0373
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Yee, Douglas
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文献类型：
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作者：
Becker, Marc A.;Ibrahim, Yasir H.;Yee, Douglas
IGF通路刺激乳腺癌细胞的恶性行为。在此，我们确定了雷帕霉素(mTOR)/S6激酶1 （S6K1）轴的哺乳动物靶点是IGF和雌激素受体(ER) α串扰的关键成分。胰岛素受体底物（IRS）接头分子在IGF-I受体下游起作用，并指示特定的生物反应，其中IRS-1驱动增殖，IRS-2与运动有关。虽然雷帕霉素诱导的mTOR抑制已被证明可以阻断igf诱导的IRS降解，但我们揭示了对运动性（上调）和增殖（下调）的不同影响。由于IRS-1和ER α表达之间的正相关被认为在IGF生长反应中发挥核心作用，我们研究了ER α作为下游mTOR靶点的潜在作用。小分子抑制和靶向敲低S6K1阻断了igf诱导的ER α (S167)磷酸化，不影响配体依赖性ER α (S118)磷酸化。抑制S6K1激酶活性进而抑制igf刺激的S6K1/ER α关联、雌激素反应元件启动子结合和ER α靶基因转录。此外，位点特异性ER α (S167)突变减少ER α靶基因转录并阻断igf诱导的集落形成。这些发现支持了IGF通路和内质网α之间的新联系，其中翻译因子S6K1影响内质网α调节基因的转录。（分子内分泌学25:516-528,2011）
The IGF pathway stimulates malignant behavior of breast cancer cells. Herein we identify the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) axis as a critical component of IGF and estrogen receptor (ER)alpha cross talk. The insulin receptor substrate (IRS) adaptor molecules function downstream of IGF-I receptor and dictate a specific biological response, in which IRS-1 drives proliferation and IRS-2 is linked to motility. Although rapamycin-induced mTOR inhibition has been shown to block IGF-induced IRS degradation, we reveal differential effects on motility (up-regulation) and proliferation (down-regulation). Because a positive correlation between IRS-1 and ER alpha expression is thought to play a central role in the IGF growth response, we investigated the potential role of ER alpha as a downstream mTOR target. Small molecule inhibition and targeted knockdown of S6K1 blocked the IGF-induced ER alpha(S167) phosphorylation and did not influence ligand-dependent ER alpha(S118) phosphorylation. Inhibition of S6K1 kinase activity consequently ablated IGF-stimulated S6K1/ER alpha association, estrogen response element promoter binding and ER alpha target gene transcription. Moreover, site-specific ER alpha(S167) mutation reduced ER alpha target gene transcription and blocked IGF-induced colony formation. These findings support a novel link between the IGF pathway and ER alpha, in which the translation factor S6K1 affects transcription of ER alpha-regulated genes. (Molecular Endocrinology 25: 516-528, 2011)