Gene amplification is a mechanism of SW overexpression in breast cancer
Gene amplification is a mechanism of SW overexpression in breast cancer
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DOI：
10.1158/0008-5472.can-04-4286
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Ford, HL
中科院分区：
文献类型：
--
作者：
Reichenberger, KJ;Coletta, RD;Ford, HL
在正常发育过程中，Six1同源蛋白通过刺激增殖和抑制凋亡，在祖细胞群的扩增中起着关键作用。在几种肿瘤类型中都观察到Six1的过度表达，这表明当在不适当的环境中表达时，Six1可能通过恢复通常赋予发育中细胞的特性而促进肿瘤发生。事实上，Six1在乳腺癌和横纹肌肉瘤中都促进肿瘤细胞增殖，并且在横纹肌肉瘤中它还与转移有关。虽然在几种肿瘤类型中都报道了Six1的过度表达，但此前尚未研究其过度表达的机制。在此我们表明基因剂量的改变可能导致Six1 mRNA的过度表达。与正常乳腺上皮细胞相比，许多乳腺癌细胞系中出现显著的Six1基因扩增和过度表达，并且基因剂量的变化与Six1 mRNA水平的升高相关。在对214例人类浸润性导管乳腺癌进行Six1基因剂量检测中，4.7%显示Six1扩增/过度表达，并且Six1基因剂量增加的肿瘤会过度表达Six1 mRNA。这些数据表明SUI基因扩增/过度表达是人类乳腺癌中Six1 mRNA过度表达的一种机制。
The Six1 homeoprotein plays a critical role in expanding progenitor populations during normal development via its stimulation of proliferation and inhibition of apoptosis. Overexpression of Six1 is observed in several tumor types, suggesting that when expressed out of context, Six1 may contribute to tumorigenesis by reinstating properties normally conveyed on developing cells. Indeed, Six1 contributes to tumor cell proliferation both in breast cancer and in rhabdomyosarcomas, in which it is also implicated in metastasis. Whereas Six1 overexpression has been reported in several tumor types, the mechanism responsible for its overexpression has not previously been examined. Here we show that a change in gene dosage may contribute to Six1 mRNA overexpression. Significant Six1 gene amplification and overrepresentation occurs in numerous breast cancer cell lines as compared with normal mammary epithelial cells, and the changes in gene dosage correlate with increased Six1 mRNA levels. Of 214 human infiltrating ductal breast carcinomas examined for Six1 gene dosage, 4.7% show Six1 amplification/ overrepresentation, and tumors that exhibit an increase in Six1 gene dosage overexpress Six1 mRNA. These data implicate SUI gene amplification/overrepresentation as a mechanism of Six1 mRNA overexpression in human breast cancer.