The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
J Cell Sci. 2010 Oct 15;123(Pt 20):3558-65. doi: 10.1242/jcs.064915.
The activating transcription factor 3 (ATF3) gene is induced by a variety of signals, including many of those encountered by cancer cells. We present evidence that ATF3 is induced by TGFβ in the MCF10CA1a breast cancer cells and plays an integral role for TGFβ to upregulate its target genes snail, slug and twist, and to enhance cell motility. Furthermore, ATF3 upregulates the expression of the TGFb gene itself, forming a positive-feedback loop for TGFβ signaling. Functionally, ectopic expression of ATF3 leads to morphological changes and alterations of markers consistent with epithelial-to-mesenchymal transition (EMT). It also leads to features associated with breast-cancer-initiating cells: increased CD24(low)-CD44(high) population of cells, mammosphere formation and tumorigenesis. Conversely, knockdown of ATF3 reduces EMT, CD24(low)-CD44(high) cells and mammosphere formation. Importantly, knocking down twist, a downstream target, reduces the ability of ATF3 to enhance mammosphere formation, indicating the functional significance of twist in ATF3 action. To our knowledge, this is the first report demonstrating the ability of ATF3 to enhance breast cancer-initiating cell features and to feedback on TGFβ. Because ATF3 is an adaptive-response gene and is induced by various stromal signals, these findings have significant implications for how the tumor microenvironment might affect cancer development.
激活转录因子 3（ATF3）基因受多种信号诱导，包括癌细胞遇到的许多信号。我们提供的证据表明，ATF3 被 TGFβ 在 MCF10CA1a 乳腺癌细胞中诱导，并为 TGFβ 上调其靶基因 snail、slug 和 twist 以及增强细胞迁移发挥重要作用。此外，ATF3 上调 TGFb 基因本身的表达，形成 TGFβ 信号的正反馈环。在功能上，ATF3 的异位表达导致与上皮-间质转化（EMT）一致的形态变化和标志物改变。它还导致与乳腺癌起始细胞相关的特征：增加细胞的 CD24(low)-CD44(high)群体、形成乳腺球体和致瘤性。相反，敲低 ATF3 减少 EMT、CD24(low)-CD44(high)细胞和乳腺球体形成。重要的是，敲低下游靶基因 twist 会降低 ATF3 增强乳腺球体形成的能力，表明 twist 在 ATF3 作用中的功能意义。据我们所知，这是第一个证明 ATF3 能够增强乳腺癌起始细胞特征并反馈 TGFβ 的报告。由于 ATF3 是一种适应性反应基因，并且受到各种基质信号的诱导，这些发现对肿瘤微环境如何影响癌症发展具有重要意义。
