TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG
TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG
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DOI：
10.1002/path.5245
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发表时间：
2019-06-01
影响因子：
7.3
通讯作者：
Tuck, Alan B.
中科院分区：
文献类型：
--
作者：
Krstic, Milica;Kolendowski, Bart;Tuck, Alan B.
乳腺上皮细胞获得细胞侵袭性并随后从导管原位癌（DCIS）转变为浸润性乳腺癌是乳腺癌进展的关键步骤。关于控制这种转变的分子动力学知之甚少。我们先前已经表明，转录调节因子TBX 3在DCIS样细胞中的过表达增加了存活、生长和侵袭性。为了进一步探索这一机制，并在高分辨率，异构体特异性的背景下评估TBX 3的直接转录靶点，我们进行了全基因组染色质免疫沉淀（ChIP）阵列结合转录组学分析。我们发现TBX 3调节几个上皮-间充质转化（EMT）相关基因，包括SLUG和TWIST 1。重要的是，我们证明了TBX 3是SLUG表达的直接调节因子，并且SLUG表达是TBX 3诱导的迁移和侵袭所必需的。通过免疫组织化学评估早期（0期和I期）乳腺癌中的TBX 3，发现在低级别病变中表达较高。在第二个独立的早期非高级别队列中，我们观察到DCIS中TBX 3水平与浸润性病灶大小之间的相关性。在浸润性癌中TBX 3与SLUG、TWIST 1表达呈正相关。途径分析显示，几种蛋白酶及其抑制剂的表达发生改变，这与体内降解基底膜的能力一致。这些发现强烈表明TBX 3通过低级别分子途径参与促进早期浸润前乳腺癌的侵袭性和进展。(c)2019作者病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
The acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high-resolution, isoform-specific context, we conducted genome-wide chromatin-immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial-mesenchymal transition (EMT)-related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3-induced migration and invasion. Assessing TBX3 by immunohistochemistry in early-stage (stage 0 and stage I) breast cancers revealed high expression in low-grade lesions. Within a second independent early-stage non-high-grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early-stage pre-invasive breast cancer to invasive carcinoma through the low-grade molecular pathway. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.