Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA.
Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA.
Sci Rep. 2021 May 4;11(1):9502. doi: 10.1038/s41598-021-88924-y.
The E2F family of transcription factors is important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis and metastasis. Alteration of the Rb/E2F pathway occurs in various forms of cancer, including breast cancer. E2F1 ablation has been shown to decrease metastasis in MMTV-Neu and MMTV-PyMT transgenic mouse models of breast cancer. Here we take a bioinformatic approach to determine the E2F1 regulated genomic alterations involved in the metastatic cascade, in both Neu and PyMT models. Through gene expression analysis, we reveal few transcriptome changes in non-metastatic E2F1 tumors relative to transgenic tumor controls. However investigation of these models through whole genome sequencing found numerous differences between the models, including differences in the proposed tumor etiology between E2F1 and E2F1 tumors induced by Neu or PyMT. For example, loss of E2F1 within the Neu model led to an increased contribution of the inefficient double stranded break repair signature to the proposed etiology of the tumors. While the SNV mutation burden was higher in PyMT mouse tumors than Neu mouse tumors, there was no statistically significant differences between E2F WT and E2F1 KO mice. Investigating mutated genes through gene set analysis also found a significant number of genes mutated in the cell adhesion pathway in E2F1 tumors, indicating this may be a route for disruption of metastasis in E2F1 tumors. Overall, these findings illustrate the complicated nature of uncovering drivers of the metastatic process.
E2F 转录因子家族对于许多细胞过程都很重要，从其在细胞周期调控中的典型作用到在血管生成和转移中的其他作用。Rb/E2F 途径的改变发生在各种形式的癌症中，包括乳腺癌。已经表明，E2F1 缺失可减少 MMTV-Neu 和 MMTV-PyMT 转基因乳腺癌小鼠模型中的转移。在这里，我们采用生物信息学方法来确定 E2F1 调节的基因组改变在 Neu 和 PyMT 模型中参与转移级联。通过基因表达分析，我们发现相对于转基因肿瘤对照，非转移性 E2F1 肿瘤中的转录组变化很少。然而，通过全基因组测序对这些模型进行研究发现，这些模型之间存在许多差异，包括 E2F1 和由 Neu 或 PyMT 诱导的 E2F1 肿瘤之间提议的肿瘤病因之间的差异。例如，在 Neu 模型中 E2F1 的缺失导致效率低下的双链断裂修复特征对肿瘤提议病因的贡献增加。虽然 PyMT 小鼠肿瘤中的 SNV 突变负担高于 Neu 小鼠肿瘤，但 E2F WT 和 E2F1 KO 小鼠之间没有统计学上的显著差异。通过基因集分析研究突变基因还发现，E2F1 肿瘤中细胞黏附途径中有大量基因发生突变，表明这可能是 E2F1 肿瘤中破坏转移的途径之一。总体而言，这些发现说明了揭示转移过程驱动因素的复杂性。
