The rapamycin-regulated gene expression signature determines prognosis for breast cancer.
The rapamycin-regulated gene expression signature determines prognosis for breast cancer.
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DOI：
10.1186/1476-4598-8-75
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发表时间：
2009-09-24
期刊：
影响因子：
37.3
通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
--
作者：
Akcakanat A;Zhang L;Tsavachidis S;Meric-Bernstam F
哺乳动物雷帕霉素靶蛋白（mTOR）是一种丝氨酸/苏氨酸激酶，参与多种促进肿瘤生长的细胞内信号通路。mTOR在很大一部分乳腺癌中被异常激活，是一个有希望的治疗靶点。雷帕霉素及其类似物正在进行乳腺癌治疗的临床试验。基因表达模式（元基因）也可用于模拟生物过程或药物治疗的效果。在这项研究中，我们验证了雷帕霉素调控的基因表达特征可以预测乳腺癌患者疾病结局的假设。集落形成、磺胺丹B （IC50 < 1 nM）和异种移植动物实验表明，MDA-MB-468细胞对雷帕霉素敏感。体外和体内基因表达数据的比较确定了一个特征，称为雷帕霉素metagene指数（RMI）， 31个基因在体外和体内被雷帕霉素治疗上调（假发现率为10%）。在Miller数据集中，RMI与肿瘤大小或淋巴结状态无关。高（bbb75百分位）RMI与较长的生存期显著相关（P = 0.015）。在多变量分析中，RMI （P = 0.029）、肿瘤大小（P = 0.015）和淋巴结状态（P = 0.001）是预后因素。在van 't Veer研究中，RMI与发生远处转移的时间无关（P = 0.41）。在Wang数据集中，RMI预测疾病复发时间（P = 0.009）。雷帕霉素调节的基因表达特征预测乳腺癌的临床结局。这支持了mTOR信号在乳腺癌生物学中的核心作用，并进一步推动了mTOR靶向治疗乳腺癌的研究。
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Colony formation and sulforhodamine B (IC50 < 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In the Wang dataset, RMI predicted time to disease relapse (P = 0.009). Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment.
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