Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer
Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer
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DOI：
10.1093/carcin/bgi379
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发表时间：
2006-07-01
期刊：
影响因子：
4.7
通讯作者：
Robertson, Keith D.
中科院分区：
文献类型：
--
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
Wnt信号通路是在许多癌症类型中失调的强大且突出的致癌机制。虽然来自转基因小鼠模型和人类肿瘤研究的证据清楚地表明，该途径在人类乳腺癌中可能具有重要性，但在这种肿瘤类型中发现的Wnt失调的确切分子性质的线索很少。在这里，我们表明，Wnt抑制因子-1（WIF 1）基因，它编码的分泌蛋白拮抗Wnt依赖性信号，靶向表观遗传沉默在人类乳腺癌。我们发现，培养的人乳腺肿瘤细胞系显示缺乏或低水平的WIF 1表达，当细胞与DNA去甲基化剂5-氮杂-2 '-脱氧胞苷一起培养时，WIF 1表达增加。此外，通过甲基化特异性PCR和亚硫酸氢盐基因组测序判断，WIF 1启动子在这些细胞中异常高甲基化。使用一组患者匹配的乳腺肿瘤和正常乳腺组织，我们表明，WIF 1表达通常减少乳腺肿瘤相比，正常组织，这与WIF 1启动子高甲基化。对一组24个原发性乳腺肿瘤的分析确定，WIF 1启动子在67%的这些肿瘤中异常甲基化，表明该基因的表观遗传沉默是人类乳腺癌中的常见事件。使用DNA甲基转移酶（DNMT）DNMT 1和/或DNMT 3B精通或缺陷的等基因细胞系小组，我们表明WIF 1启动子的超甲基化归因于DNMT 1和DNMT 3B的协同活性。我们的研究结果确立了WIF 1基因作为乳腺癌中表观遗传沉默的靶点，并提供了Wnt信号转导失调与乳腺肿瘤发生之间的机制联系。
The Wnt signaling pathway is a powerful and prominent oncogenic mechanism dysregulated in numerous cancer types. While evidence from transgenic mouse models and studies of human tumors clearly indicate that this pathway is of likely importance in human breast cancer, few clues as to the exact molecular nature of Wnt dysregulation have been uncovered in this tumor type. Here, we show that the Wnt inhibitory factor-1 (WIF1) gene, which encodes a secreted protein antagonistic to Wnt-dependent signaling, is targeted for epigenetic silencing in human breast cancer. We show that cultured human breast tumor cell lines display absent or low levels of WIF1 expression that are increased when cells are cultured with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, the WIF1 promoter is aberrantly hypermethylated in these cells as judged by both methylation-specific PCR and bisulfite genomic sequencing. Using a panel of patient-matched breast tumors and normal breast tissue, we show that WIF1 expression is commonly diminished in breast tumors when compared with normal tissue and that this correlates with WIF1 promoter hypermethylation. Analysis of a panel of 24 primary breast tumors determined that the WIF1 promoter is aberrantly methylated in 67% of these tumors, indicating that epigenetic silencing of this gene is a frequent event in human breast cancer. Using an isogenic panel of cell lines proficient or deficient in the DNA methyltransferases (DNMTs) DNMT1 and/or DNMT3B, we show that hypermethylation of the WIF1 promoter is attributable to the cooperative activity of both DNMT1 and DNMT3B. Our findings establish the WIF1 gene as a target for epigenetic silencing in breast cancer and provide a mechanistic link between the dysregulation of Wnt signaling and breast tumorigenesis.