Reference SummaryHollern DP, Mol Cell Biol 2014 Sep;34(17):3229-43

Title

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

Authors

 Hollern DP; Honeysett J; Cardiff RD; Andrechek ER

Journal

 Mol Cell Biol

Volume

 34

Issue

 17

Year

 2014

Pages

 3229-43

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.

Links

 J:224271 – MGI References
24934442 – National Library of Medicine/PubMed

Strain Notes

Strain Note
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul All mice in this study were stated to be "in the FVB background".
This cohort of mice was generated by breeding FVB/N-Tg(MMTV-PyVT)634Mul/J mice (from Jackson Lab) to E2f1 mutant mice.
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul All mice in this study were stated to be "in the FVB background".
This cohort of mice was generated by breeding FVB/N-Tg(MMTV-PyVT)634Mul/J mice (from Jackson Lab) to E2f2 mutant mice.
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul All mice in this study were stated to be "in the FVB background".
This cohort of mice was generated by breeding FVB/N-Tg(MMTV-PyVT)634Mul/J mice (from Jackson Lab) to E2f3 mutant mice.
FVB/N-Tg(MMTV-PyVT)634Mul All mice in this study were stated to be "in the FVB background".

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

50 - 100
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

50 - 100
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

50 - 100
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

50 - 100
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - adenosquamous Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - adenosquamous Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - adenosquamous Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - adenosquamous Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - glandular Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - glandular Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - glandular Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - glandular Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar/adenosquamous Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar/adenosquamous Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar/adenosquamous Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - microacinar/adenosquamous Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - mixed Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - mixed Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - mixed Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - mixed Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - papillary Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - papillary Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - papillary Mammary gland

observed
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - papillary Mammary gland

observed
FVB/N-Tg(MMTV-PyVT)634Mul Mammary gland tumor - solid Mammary gland

observed
FVB/N-E2f1tm1Meg Tg(MMTV-PyVT)634Mul Mammary gland tumor - solid Mammary gland

observed
FVB/N-E2f2tm1Zubi Tg(MMTV-PyVT)634Mul Mammary gland tumor - solid Mammary gland

0
FVB/N-E2f3tm1Lees/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor - solid Mammary gland

observed