title: Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.
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.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Kent
authors.forename: Sooin
authors.initials: S
authors.lastname: Bae
authors.forename: Shih-Yin
authors.initials: SY
authors.lastname: Tsai
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.forename: Arunima
authors.initials: A
authors.lastname: Srivastava
authors.forename: Christopher
authors.initials: C
authors.lastname: Koivisto
authors.forename: Chelsea K
authors.initials: CK
authors.lastname: Martin
authors.forename: Elisa
authors.initials: E
authors.lastname: Ridolfi
authors.forename: Grace C
authors.initials: GC
authors.lastname: Miller
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Zorko
authors.forename: Emilia
authors.initials: E
authors.lastname: Plevris
authors.forename: Yannis
authors.initials: Y
authors.lastname: Hadjiyannis
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez
authors.forename: Eric
authors.initials: E
authors.lastname: Nolan
authors.forename: Raleigh
authors.initials: R
authors.lastname: Kladney
authors.forename: Bart
authors.initials: B
authors.lastname: Westendorp
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Kamal S
authors.initials: KS
authors.lastname: Pohar
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D052138:Genes, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C490840:E2f3 protein, mouse; D009363:Neoplasm Proteins