The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Abstract

While the E2F transcription factors have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the MMTV-PyMT mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with the knockouts of E2F1, E2F2 and E2F3. With the ablation of individual E2Fs we noted alteration of tumor latency, histology, and vasculature. Interestingly, we noted a striking reduction in metastatic capacity and circulating tumor cells in both E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of Vegfa, Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control expression of genes critical to angiogenesis, remodeling of the extracellular matrix, tumor cell survival and tumor cell interactions with vascular endothelial cells to facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors have key roles in mediating tumor development and metastasis in addition to their well characterized roles in cell cycle control.