Pacher Margit, Seewald Michael J, Mikula Mario, Oehler Susanne, Mogg Maurice, Vinatzer Ursula, Eger Andreas, Schweifer Norbert, Varecka Roland, Sommergruber Wolfgang, Mikulits Wolfgang, Schreiber Martin
Department of Obstetrics and Gynecology, Medical University of Vienna, A-1090 Vienna, Austria.
Carcinogenesis. 2007 Jan;28(1):49-59. doi: 10.1093/carcin/bgl091. Epub 2006 Jun 14.
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.
胰岛素样生长因子（IGF）信号传导是乳腺发育和乳腺癌的关键调节因子。我们分析了17个人类乳腺癌细胞系和4个乳腺上皮细胞系中IGF信号级联的表达情况。5个细胞系高水平表达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信号传导存在共同激活。接下来，我们在MCF7乳腺癌细胞中稳定过表达IGF1和IGF2，这并未影响其上皮特征以及上皮标记基因E-钙黏蛋白和β-连环蛋白的表达与定位。相反，在小鼠异种移植实验中，IGF1和IGF2过表达显著提高了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未发生改变。利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发现，21个基因在IGF1和IGF2作用下均上调超过2倍，9个基因在IGF1作用下上调，9个基因在IGF2作用下上调。发现上调的基因中有一半参与氨基酸的转运和生物合成，包括几种氨基酸转运蛋白、精氨琥珀酸合酶和天冬酰胺合成酶，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速率的刺激作用。我们得出结论，长期IGF刺激诱导细胞增殖和肿瘤形成可能主要归因于合成代谢效应，特别是氨基酸产生和摄取的增加。
