Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer
Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer
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DOI：
10.1038/sj.onc.1209470
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发表时间：
2006-07-20
期刊：
影响因子：
8
通讯作者：
Sakanaka, C.
中科院分区：
文献类型：
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作者：
Shulewitz, M.;Soloviev, I.;Sakanaka, C.
Wnt通路基因的突变在人类乳腺癌中是罕见的，然而该通路的激活从β-连环蛋白的错位定位是明显的。我们搜索了Wnt途径基因表达的关系，发现相对于正常乳腺组织，分泌型卷曲相关蛋白1（Sfrp 1）和TCF-4转录本在乳腺癌的常见子集中均高度下调。Sfrp 1先前已被表征为Wnt抑制剂，并且我们发现干扰其在人乳腺上皮细胞系MCF 10A中的表达可激活Wnt信号传导。乳腺癌中TCF-4水平的降低是令人惊讶的，因为它是响应Wnt信号传导的转录因子。因此，我们研究了TCF-4在人乳腺细胞中可能的抑制作用，并进一步表征了Sfrp 1。我们将CD 24鉴定为MCF 10A细胞中的Wnt靶标，并将其表达用作Wnt信号传导的标志物。在该细胞系中干扰Sfrp 1或TCF-4增强了CD 24表达。此外，去除CD 24-荧光素酶报告基因中的TCF/LEF结合位点导致报告基因表达升高。我们的研究结果表明，Sfrp 1和TCF-4抑制乳腺组织中的Wnt信号传导，它们的下调有助于Wnt信号传导的激活。
Mutations in Wnt pathway genes are rare in human breast cancer, yet activation of the pathway is evident from the misolocalization of beta-catenin. We searched for relationships in the expression of Wnt pathway genes and found that both secreted frizzled related protein 1 (Sfrp1) and TCF-4 transcripts were all highly downregulated in a common subset of breast cancers relative to normal breast tissue. Sfrp1 has been previously characterized as a Wnt inhibitor, and we found that interfering with its expression in the human mammary epithelial cell line MCF10A activated Wnt signaling. Reduction of TCF-4 levels in breast cancer was surprising as it is a transcription factor that is responsive to Wnt signaling. Therefore, we investigated a possible inhibitory role for TCF-4 in human breast cells as well as further characterizing Sfrp1. We identified CD24 as a Wnt target in MCF10A cells and used its expression a marker of Wnt signaling. Interfering with either Sfrp1 or TCF-4 in this cell line enhanced CD24 expression. Furthermore, removal of TCF/LEF binding sites in a CD24-luciferase reporter resulted in elevated reporter gene expression. Our results indicate that both Sfrp1 and TCF-4 repress Wnt signaling in breast tissue and their downregulation contributes to the activation of Wnt signaling.