title: Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis.
abstract: Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3(-/loxP) mammary glands revealed that there is a selection against E2f3(-/-) cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Simmons
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cleghorn
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Goldenberg
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sites
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sandy
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Trimboli
authors.affiliation: Center for Biostatistics, Ohio State University, Columbus, OH, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.affiliation: Division of Hematology & Oncology, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shapiro
authors.affiliation: 1] Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA [2] Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA [3] Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Leone
mesh_terms: D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D063646:Carcinogenesis; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D050703:E2F2 Transcription Factor / Q000378:metabolism*; D050699:E2F3 Transcription Factor / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; C490840:E2f3 protein, mouse; C524056:Erbb2 protein, mouse