SOX4 Induces Epithelial-Mesenchymal Transition and Contributes to Breast Cancer Progression
SOX4 Induces Epithelial-Mesenchymal Transition and Contributes to Breast Cancer Progression
复制标题
SOX4 诱导上皮间质转化并促进乳腺癌进展。
DOI：
10.1158/0008-5472.can-12-1045
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发表时间：
2012-09-01
期刊：
影响因子：
11.2
通讯作者：
Huang, Baiqu
中科院分区：
文献类型：
--
作者：
Zhang, Jianchao;Liang, Qian;Huang, Baiqu
上皮-间充质转化(EMT)是一种发育过程，与乳腺癌的进展和转移有关。在这里，我们报告了Sox4在永生化的人乳腺上皮细胞中的异位过表达足以获得间充质特征、增强细胞迁移和侵袭，以及由CD44(高)/CD24(低)细胞亚群定义的上皮干细胞特性。SOX4正向调节已知的子宫内膜转化诱导物的表达，也激活转化生长因子-β途径参与子宫内膜上皮细胞转化。SOX4本身是由转化生长因子-β诱导的乳腺上皮细胞，是转化生长因子-β诱导内皮细胞转化所必需的。小鼠异种移植实验表明，Sox4与致癌RAS在体内协同促进肿瘤的形成。最后，在人类乳腺癌的临床标本中，我们发现Sox4异常过表达，并与三阴性乳腺癌亚型(ER(-)/PR(-)/HER2(-))相关。我们的发现通过协调EMT定义了Sox4在乳腺癌进展中的一个重要功能，并暗示该基因产物是乳腺癌预后不良的标志。
Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with breast cancer progression and metastasis. Here, we report that ectopic overexpression of SOX4 in immortalized human mammary epithelial cells is sufficient for acquisition of mesenchymal traits, enhanced cell migration, and invasion, along with epithelial stem cell properties defined by the presence of a CD44(high)/CD24(low) cell subpopulation. SOX4 positively regulated expression of known EMT inducers, also activating the TGF-β pathway to contribute to EMT. SOX4 itself was induced by TGF-β in mammary epithelial cells and was required for TGF-β-induced EMT. Murine xenograft experiments showed that SOX4 cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in clinical specimens of human breast cancer, we found that SOX4 was abnormally overexpressed and correlated with the triple-negative breast cancer subtype (ER(-)/PR(-)/HER2(-)). Our findings define an important function for SOX4 in the progression of breast cancer by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease.