Reference SummaryKent LN, J Clin Invest 2017 Mar 01;127(3):830-842

Title

 Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

Authors

 Kent LN; Bae S; Tsai SY; Tang X; Srivastava A; Koivisto C; Martin CK; Ridolfi E; Miller GC; Zorko SM; Plevris E; Hadjiyannis Y; Perez M; Nolan E; Kladney R; Westendorp B; de Bruin A; Fernandez S; Rosol TJ; Pohar KS; Pipas JM; Leone G

Journal

 J Clin Invest

Volume

 127

Issue

 3

Year

 2017

Pages

 830-842

Abstract

 Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.

Links

 J:242936 – MGI References
28134624 – National Library of Medicine/PubMed

Strain Notes

Strain Note
FVB.129S4-E2f1tm1Meg These mice had been backcrossed five times to "FVB/NT". [Note: The "T" may be an erroneous indication of Taconic, lab code "Tac".]
FVB.129S6-E2f3tm2.1Gle These mice had been backcrossed five times to "FVB/NT". [Note: The "T" may be an erroneous indication of Taconic, lab code "Tac".]
FVB.129S6-E2f3tm3.1Gle These mice had been backcrossed seven times to "FVB/NT". [Note: The "T" may be an erroneous indication of Taconic, lab code "Tac".]
[not specified] This cohort represents pooled data for wild-type littermates of a variety of E2f mutant strains.
[not specified]-E2f3tm5(E2f1)Gle/? Lyz2tm1(cre)Ifo/? Data was pooled for mice heterozygous and homozygous for the E2f3 knock-in allele. The reference did not specify if the mice were heterozygous or homozygous for the Lys-cre allele.
[not specified]-E2f3tm5(E2f1)Gle/? Speer6-ps1Tg(Alb-cre)21Mgn/? Data was pooled for mice heterozygous and homozygous for the E2f3 knock-in allele, all carrying at least one copy of the Alb-cre transgene.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified] Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Uterus

3.2
STOCK E2f3tm4Gle Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Uterus

5.6
STOCK E2f3tm5(E2f1)Gle/+ Liver adenoma Liver

5.0
STOCK E2f3tm5(E2f1)Gle Liver adenoma Liver

4.3 - 6.25
STOCK E2f3tm4Gle/+ Liver adenoma Liver

5.0
STOCK E2f1tm1Meg E2f3tm5(E2f1)Gle Liver adenoma Liver

29
[not specified] Liver hepatocellular carcinoma
  • diethylnitrosamine (DEN)
 Liver

0 - 94
[not specified] Liver hepatocellular carcinoma Liver

0 - 8.7
FVB.129S4-E2f1tm1Meg Liver hepatocellular carcinoma
  • diethylnitrosamine (DEN)
 Liver

5.0 - 36
FVB.129S6-E2f3tm2.1Gle Liver hepatocellular carcinoma
  • diethylnitrosamine (DEN)
 Liver

76 - 88
FVB.129S6-E2f3tm2.1Gle Liver hepatocellular carcinoma Liver

0
FVB.129S6-E2f3tm3.1Gle Liver hepatocellular carcinoma
  • diethylnitrosamine (DEN)
 Liver

61 - 90
STOCK E2f3tm5(E2f1)Gle/+ Liver hepatocellular carcinoma Liver

50 - 58
STOCK E2f3tm5(E2f1)Gle Liver hepatocellular carcinoma Liver

64 - 87.5
STOCK E2f3tm5(E2f1)Gle Liver hepatocellular carcinoma
  • diethylnitrosamine (DEN)
 Liver

80 - 100
STOCK E2f3tm4Gle/+ Liver hepatocellular carcinoma Liver

31 - 40
STOCK E2f3tm4Gle Liver hepatocellular carcinoma Liver

56 - 72
STOCK E2f1tm1Meg/+ E2f3tm5(E2f1)Gle Liver hepatocellular carcinoma Liver

22
STOCK E2f1tm1Meg E2f3tm5(E2f1)Gle Liver hepatocellular carcinoma Liver

0
[not specified]-E2f3tm5(E2f1)Gle/? Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hepatocellular carcinoma Liver

0
[not specified]-E2f3tm5(E2f1)Gle/? Lyz2tm1(cre)Ifo/? Liver hepatocellular carcinoma Liver

45 - 60
STOCK E2f3tm5(E2f1)Gle Liver tumor Liver

observed - 94
STOCK E2f3tm5(E2f1)Gle Liver tumor
  • polyinosinic/polycytidylic acid (pIpC) (poly I:C)
 Liver

observed
[not specified]-E2f3tm5(E2f1)Gle Tg(Mx1-cre)1Cgn Liver tumor Liver

observed
[not specified]-E2f3tm5(E2f1)Gle Tg(Mx1-cre)1Cgn Liver tumor
  • polyinosinic/polycytidylic acid (pIpC) (poly I:C)
 Liver

observed
[not specified] Lung tumor Lung

13
STOCK E2f3tm4Gle Lung tumor Lung

5.6 - 11
[not specified] Stomach tumor Stomach

4.3
FVB.129S6-E2f3tm2.1Gle (Unspecified organ) tumor (Unspecified organ)

0