The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer.

Abstract

While the E2F transcription factors (E2Fs) 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 mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (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 E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control.

• Authors: Daniel P Hollern, Jordan Honeysett, Robert D Cardiff, Eran R Andrechek
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 34 Issue 17 Pg. 3229-43 (Sep 2014) ISSN: 1098-5549 [Electronic] United States
• PMID: 24934442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antigens, Polyomavirus Transforming
• E2F Transcription Factors
• E2F1 Transcription Factor
• E2F2 Transcription Factor
• E2F3 Transcription Factor
• E2f1 protein, mouse
• E2f2 protein, mouse
• E2f3 protein, mouse

Topics

• Animals
• Antigens, Polyomavirus Transforming
• E2F Transcription Factors (deficiency, genetics, physiology)
• E2F1 Transcription Factor (deficiency, genetics, physiology)
• E2F2 Transcription Factor (deficiency, genetics, physiology)
• E2F3 Transcription Factor (deficiency, genetics, physiology)
• Female
• Humans
• Lung Neoplasms (genetics, pathology, secondary)
• Mammary Neoplasms, Experimental (etiology, pathology, secondary)
• Mammary Tumor Virus, Mouse
• Mice
• Mice, Knockout
• Neoplastic Cells, Circulating (pathology)
• Neovascularization, Pathologic (genetics)
• Retroviridae Infections (etiology, pathology)
• Signal Transduction
• Tumor Microenvironment
• Tumor Virus Infections (etiology, pathology)