ΔNp63α Promotes Breast Cancer Cell Motility through the Selective Activation of Components of the Epithelial-to-Mesenchymal Transition Program.
ΔNp63α Promotes Breast Cancer Cell Motility through the Selective Activation of Components of the Epithelial-to-Mesenchymal Transition Program.
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DOI：
10.1158/0008-5472.can-14-3363
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发表时间：
2015-09-15
期刊：
影响因子：
11.2
通讯作者：
Pearson GW
中科院分区：
文献类型：
--
作者：
Dang TT;Esparza MA;Maine EA;Westcott JM;Pearson GW
细胞身份信号影响肿瘤细胞的侵袭能力，正如恶性进展过程中上皮间质转化（EMT）程序的选择所证明的那样。乳腺癌细胞保留了典型的上皮特征，并作为有粘性的细胞群集体侵袭，但对其侵袭能力至关重要的信号通路仍不完全清楚。在这里，我们报道转录因子 ΔNp63α 通过诱导混合间充质/上皮状态来驱动基底样乳腺癌 (BLBC) 细胞的迁移。通过对多个 BLBC 细胞群的表达分析和功能测试相结合，我们确定 ΔNp63α 通过提高 EMT 程序组件 Slug 和 Axl 的表达来诱导迁移。有趣的是，ΔNp63α还增加了miR205的表达，miR205可以沉默ZEB1/2以防止EMT诱导引起的上皮特征丧失。在临床样本中，ΔNp63α 通路各个元件的共表达证实了其在 BLBC 运动信号传导中的意义。我们观察到 ΔNp63α 通路的激活发生在非浸润性导管原位癌向浸润性乳腺癌的转变过程中。值得注意的是，在原位肿瘤模型中，Slug 表达足以诱导表达 E-钙粘蛋白的 BLBC 细胞的集体侵袭。总之，我们的结果说明了 ΔNp63α 如何通过选择性地参与 EMT 程序的促迁移成分来驱动乳腺癌细胞侵袭，同时仍然促进上皮特征的保留。
Cell identity signals influence the invasive capability of tumor cells, as demonstrated by the selection for programs of epithelial-to-mesenchymal transition (EMT) during malignant progression. Breast cancer cells retain canonical epithelial traits and invade collectively as cohesive groups of cells, but the signaling pathways critical to their invasive capabilities are still incompletely understood. Here we report that the transcription factor ΔNp63α drives the migration of basal-like breast cancer (BLBC) cells by inducing a hybrid mesenchymal/epithelial state. Through a combination of expression analysis and functional testing across multiple BLBC cell populations, we determined that ΔNp63α induces migration by elevating the expression of the EMT program components Slug and Axl. Interestingly, ΔNp63α also increased the expression of miR205, which can silence ZEB1/2 to prevent the loss of epithelial character caused by EMT induction. In clinical specimens, co-expression of various elements of the ΔNp63α pathway confirmed its implication in motility signaling in BLBC. We observed that activation of the ΔNp63α pathway occurred during the transition from noninvasive ductal carcinoma in situ to invasive breast cancer. Notably, in an orthotopic tumor model, Slug expression was sufficient to induce collective invasion of E-cadherin expressing BLBC cells. Together, our results illustrate how ΔNp63α can drive breast cancer cell invasion by selectively engaging pro-migratory components of the EMT program while, in parallel, still promoting the retention of epithelial character.