Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

Abstract

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. 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.