Oh Annabell, List Heinz-Joachim, Reiter Ronald, Mani Aparna, Zhang Ying, Gehan Edmund, Wellstein Anton, Riegel Anna T
Department of Oncology, Vincent T. Lombardi Cancer Center, Georgetown University, Washington, District of Columbia 20057, USA.
Cancer Res. 2004 Nov 15;64(22):8299-308. doi: 10.1158/0008-5472.CAN-04-0354.
The nuclear receptor coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I-stimulated anchorage-independent growth by reducing IGF-I-dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I-stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I-induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling.
核受体辅激活因子AIB1（乳腺癌中扩增基因1）在人类乳腺癌中过表达，是雌激素信号传导所必需的。然而，AIB1在乳腺癌病因学中的作用尚不清楚。在此，我们表明AIB1对人乳腺癌细胞中胰岛素样生长因子I（IGF-I）依赖性表型变化和基因表达具有限速作用。通过小干扰RNA降低MCF-7乳腺癌细胞中内源性AIB1水平，可通过减少IGF-I依赖性抗失巢凋亡来阻止IGF-I刺激的非锚定依赖性生长。基因表达的cDNA阵列和免疫印迹分析表明，AIB1水平降低导致几个控制细胞周期和凋亡的基因表达显著下降。在存在雌激素拮抗剂的情况下也观察到了这些AIB1依赖性变化，并在雌激素受体阴性细胞系MDA MB-231中得到证实。AIB1减少降低了MCF-7细胞中IGF-I受体和IRS-1的表达，但在MDA MB-231细胞中未降低。AIB1小干扰RNA处理降低了IGF-I刺激的AKT激活，而IGF-I对丝裂原活化蛋白激酶（细胞外信号调节激酶1/2）的激活未受影响。我们得出结论，AIB1是人类乳腺癌细胞中IGF-I诱导增殖、信号传导、细胞存活和基因表达所必需的，与其在雌激素受体信号传导中的作用无关。
