Zacksenhaus E, Liu J C, Jiang Z, Yao Y, Xia L, Shrestha M, Ben-David Y
Toronto General Research Institute, University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
Adv Protein Chem Struct Biol. 2017;107:223-273. doi: 10.1016/bs.apcsb.2016.10.003. Epub 2016 Dec 12.
Multiplatform genomic analyses have identified 93 frequently altered genes in breast cancer. Of these, as many as 49 genes are directly or indirectly involved in transcription. These include constitutive and inducible DNA-binding transcription factors (DB-TFs, 13 genes), corepressors/coactivators (14 genes), epigenetic (10), and mediator/splicing/rRNA (3) factors. At least nine additional genes are immediate upstream regulators of transcriptional cofactors. G:profiler analysis reveals that these alterations affect cell cycle, development/differentiation, steroid hormone, and chromatin modification pathways. A notable observation is that DB-TFs that mediate major oncogenic signaling (e.g., WNT, receptor tyrosine kinase (RTK), NOTCH, and HIPPO), which switch from default repression (signal OFF) to transcriptional activation (signal ON), are not altered in breast cancer. Instead, corepressors (e.g., pRb for E2F1 downstream of various proliferation signals) or upstream factors (e.g., APC and AXIN for TCF, downstream of canonical WNT signaling) are lost, or coactivators (e.g., NOTCH1/2 for CSL/RBPJk) are induced. In contrast, constitutive (MYC, TBX3) and signal-induced (TP53, FOXA1) DB-TFs that do not mediate default repression are directly altered in breast cancer. Some of these TFs have been implicated in the establishment of super-enhancers and positive transcriptional elongation. In addition, oncogenic transcription is induced by mutations affecting regulatory elements or chromatin conformation that create new TF-binding sites in promoters and enhancers of oncogenic genes to promote tumorigenesis. Here we review these diverse oncogenic alterations in TFs in BC and discuss implications for therapy.
多平台基因组分析已确定乳腺癌中有93个经常发生改变的基因。其中，多达49个基因直接或间接参与转录。这些基因包括组成型和诱导型DNA结合转录因子（DB-TF，13个基因）、共抑制因子/共激活因子（14个基因）、表观遗传因子（10个）以及中介体/剪接/rRNA因子（3个）。至少还有9个基因是转录辅因子的直接上游调节因子。G:profiler分析表明，这些改变影响细胞周期、发育/分化、类固醇激素和染色质修饰途径。一个值得注意的观察结果是，介导主要致癌信号（如WNT、受体酪氨酸激酶（RTK）、NOTCH和HIPPO）的DB-TF，其从默认抑制（信号关闭）转变为转录激活（信号开启），在乳腺癌中并未发生改变。相反，共抑制因子（如各种增殖信号下游E2F1的pRb）或上游因子（如经典WNT信号下游TCF的APC和AXIN）缺失，或共激活因子（如CSL/RBPJk的NOTCH1/2）被诱导。相比之下，不介导默认抑制的组成型（MYC、TBX3）和信号诱导型（TP53、FOXA1）DB-TF在乳腺癌中直接发生改变。其中一些转录因子与超级增强子的建立和正向转录延伸有关。此外，致癌转录是由影响调控元件或染色质构象的突变诱导的，这些突变在致癌基因的启动子和增强子中产生新的转录因子结合位点，从而促进肿瘤发生。在这里，我们综述了乳腺癌中转录因子的这些不同致癌改变，并讨论了其对治疗的意义。
