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

Daniel P. Hollern, Jordan Honeysett, Robert Cardiff, Eran R. Andrechek

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3229-3243
Number of pages15
JournalMolecular and Cellular Biology
Volume34
Issue number17
DOIs
StatePublished - Jan 1 2014

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E2F Transcription Factors
Breast Neoplasms
Neoplasm Metastasis
Mouse mammary tumor virus
Neoplasms
Polyomavirus
Oncogene Proteins
Cell Cycle Checkpoints
Circulating Neoplastic Cells
Gene Expression
Knockout Mice
Cell Communication
Vascular Endothelial Growth Factor A
Extracellular Matrix
Cell Survival
Histology
Endothelial Cells
Lung
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer. / Hollern, Daniel P.; Honeysett, Jordan; Cardiff, Robert; Andrechek, Eran R.

In: Molecular and Cellular Biology, Vol. 34, No. 17, 01.01.2014, p. 3229-3243.

Research output: Contribution to journalArticle

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