Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells
Impact of constitutive IGF1/IGF2 stimulation on the transcriptional program of human breast cancer cells
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DOI：
10.1093/carcin/bgl091
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发表时间：
2007-01-01
期刊：
影响因子：
4.7
通讯作者：
Schreiber, Martin
中科院分区：
文献类型：
--
作者：
Pacher, Margit;Seewald, Michael J.;Schreiber, Martin
胰岛素样生长因子 (IGF) 信号是乳腺发育和乳腺癌的关键调节因子。我们分析了 17 种人类乳腺癌和 4 种乳腺上皮细胞系中 IGF 信号级联的表达。五个细胞系表达高水平的 IGF1 受体、胰岛素 (INS)/IGF 受体底物 1、IGF 结合蛋白 2 和 4，以及雌激素受体 (ESR)，表明 IGF 和 ESR 信号传导共同激活。接下来，我们在MCF7乳腺癌细胞中稳定过表达IGF1和IGF2，这并不影响其上皮特征以及上皮标记基因E-cadherin和β-catenin的表达和定位。相反，在小鼠异种移植实验中，IGF1和IGF2过度表达可有效增加细胞增殖率和肿瘤形成效率，而对紫杉醇等化疗药物的耐药性却没有改变。使用全基因组寡核苷酸微阵列对过表达细胞进行表达谱分析，结果显示 21 个基因被 IGF1 和 IGF2 上调超过 2 倍，其中 9 个基因被 IGF1 上调，9 个基因被 IGF2 上调。发现上调的基因中有一半涉及氨基酸的转运和生物合成，包括几种氨基酸转运蛋白、精氨琥珀酸和天冬酰胺合成酶以及甲硫氨酰-tRNA 合成酶。这些基因的上调构成了一种新机制，显然有助于 IGF 信号传导对整体蛋白质合成率的刺激作用。我们的结论是，长期 IGF 刺激诱导细胞增殖和肿瘤形成可能主要是由于合成代谢作用，特别是氨基酸产生和吸收的增加。
Insulin-like growth factor (IGF) signaling is a key regulator of breast development and breast cancer. We have analyzed the expression of the IGF signaling cascade in 17 human breast cancer and 4 mammary epithelial cell lines. Five cell lines expressed high levels of IGF1 receptor, insulin (INS)/IGF receptor substrate 1, IGF-binding proteins 2 and 4, as well as the estrogen receptor (ESR), indicating a co-activation of IGF and ESR signaling. Next, we stably overexpressed IGF1 and IGF2 in MCF7 breast cancer cells, which did not affect their epithelial characteristics and the expression and localization of the epithelial marker genes E-cadherin and beta-catenin. Conversely, IGF1 and IGF2 overexpression potently increased cellular proliferation rates and the efficiency of tumor formation in mouse xenograft experiments, whereas the resistance to chemotherapeutic drugs such as taxol was unaltered. Expression profiling of overexpressing cells with whole-genome oligonucleotide microarrays revealed that 21 genes were upregulated > 2-fold by both IGF1 and IGF2, 9 by IGF1, and 9 by IGF2. Half of the genes found to be upregulated are involved in transport and biosynthesis of amino acids, including several amino acid transport proteins, argininosuccinate and asparagine synthetases, and methionyl-tRNA synthetase. Upregulation of these genes constitutes a novel mechanism apparently contributing to the stimulatory effects of IGF signaling on the global protein synthesis rate. We conclude that the induction of cell proliferation and tumor formation by long-term IGF stimulation may primarily be due to anabolic effects, in particular increased amino acid production and uptake.