Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China.
J Biol Chem. 2012 Sep 28;287(40):33533-44. doi: 10.1074/jbc.M112.392332. Epub 2012 Aug 8.
The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
乳腺癌转移的功能基因组分析的应用已经导致越来越多的器官特异性转移基因的鉴定，这些基因通常协同作用，促进转移级联的不同步骤。然而，控制这些转移基因表达的基因调控网络在很大程度上仍然未知。在这里，我们展示了一种用于反卷积转录网络以发现乳腺癌骨转移主调控因子的计算方法。在我们的分析中鉴定了几种已知的乳腺癌骨转移调节剂，如 Smad4 和 HIF1。对网络的实验验证揭示了 BACH1，一种碱性亮氨酸拉链转录因子，是包括 MMP1 和 CXCR4 在内的几个功能转移基因的共同调节因子。BACH1 的异位表达增强了乳腺癌细胞的恶性程度，相反，BACH1 的敲低显著降低了骨转移。BACH1 的表达及其靶基因与患者乳腺癌复发的高风险相关。这项研究确立了 BACH1 是乳腺癌骨转移的主调控因子，并为在复杂病理过程中识别分子决定因素提供了范例。
