Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro cells: a microarray approach.
Letrozole-, anastrozole-, and tamoxifen-responsive genes in MCF-7aro cells: a microarray approach.
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MCF-7aro 细胞中的来曲唑、阿那曲唑和他莫昔芬响应基因：微阵列方法。
DOI：
10.1158/1541-7786.mcr-04-0122
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Chen,Shiuan
中科院分区：
文献类型：
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作者：
Itoh,Toru;Karlsberg,Kim;Kijima,Ikuko;Yuan,Yate-Ching;Smith,David;Ye,Jingjing;Chen,Shiuan
抗雌激素和芳香化酶抑制剂是治疗雌激素依赖性乳腺癌的重要药物。为了研究这些药物对乳腺癌细胞中基因表达的影响，我们用睾酮、17β-雌二醇、两种芳香化酶抑制剂（来曲唑和阿那曲唑）和一种抗雌激素（他莫昔芬）稳定地处理了雌激素受体阳性、转染了芳香化酶基因的MCF-7细胞（MCF-7aro细胞）。我们发现睾酮或17β-雌二醇诱导MCF-7aro细胞的增殖速度比未处理的细胞快6倍。此外，来曲唑、阿那曲唑或他莫昔芬可有效抑制睾酮诱导的MCF-7aro细胞增殖。对Affymetrix Human Genome U133A GeneChips （Affymetrix, Santa Clara， CA）进行微阵列分析，使用从对照细胞和处理细胞中分离的总RNA。在错误发现率为0.05，最小倍数变化标准为1.5的条件下，鉴定出雄激素和雌激素同时上调的基因有104个，下调的基因有109个。超过50%的激素调节基因被所有三种抑制剂逆转，超过90%的激素调节基因被至少一种抑制剂逆转。比较每种抑制剂对基因表达的影响，我们观察到来曲唑和阿那曲唑与他莫昔芬治疗相比，在影响基因方面更相似。为了验证从微阵列分析中鉴定的基因表达谱，采用Northern分析检测了13个代表性基因的表达模式。最后，根据基因的表达模式和生物学功能/途径对具有统计学意义的基因进行分类。本研究结果为我们在分子水平上更好地理解芳香化酶抑制剂和抗雌激素的作用提供了依据。我们相信，这项研究的结果是确定药物治疗后独特表达模式的第一步，这最终将有助于定制激素依赖性乳腺癌的患者治疗策略。
Antiestrogens and aromatase inhibitors are important drugs in the treatment of estrogen-dependent breast cancer. To investigate the effects of these drugs on gene expression in breast cancer cells, we treated estrogen receptor–positive MCF-7 cells stably transfected with the aromatase gene (known as MCF-7aro cells) with testosterone, 17β-estradiol, two aromatase inhibitors (letrozole and anastrozole), and an antiestrogen (tamoxifen). We found that testosterone or 17β-estradiol induced the proliferation of MCF-7aro cells at a rate six times faster than the untreated cells. In addition, the testosterone-induced proliferation of MCF-7aro cells was effectively suppressed by letrozole, anastrozole, or tamoxifen. Microarray analyses on Affymetrix Human Genome U133A GeneChips (Affymetrix, Santa Clara, CA) were carried out using total RNA isolated from the control and treated cells. At the false discovery rate of 0.05 and a minimum fold-change criteria of 1.5, 104 genes were identified that were up-regulated and 109 genes were identified that were down-regulated by both androgen and estrogen. More than 50% of these hormone-regulated genes were counterregulated by all three inhibitors and >90% were counterregulated by at least one of the inhibitors. Comparing the effect of each inhibitor on gene expression, we observed that letrozole and anastrozole are more similar in terms of the genes they affect compared with treatment with tamoxifen. To validate the gene expression profiles identified from microarray analyses, the expression patterns of 13 representative genes were examined by Northern analysis. Finally, the genes identified as statistically significant were classified based on their expression patterns and biological function/pathways. The results of this study provide us with a better understanding of the actions of both aromatase inhibitors and antiestrogens at the molecular level. We believe that the results of this study serve as the first step in identifying unique expression patterns following drug treatment, and that this will ultimately be useful in customizing patient treatment strategies for hormone-dependent breast cancer.