title: E2F1 in melanoma progression and metastasis.
abstract: Metastases are responsible for cancer deaths, but the molecular alterations leading to tumor progression are unclear. Overexpression of the E2F1 transcription factor is common in high-grade tumors that are associated with poor patient survival. To investigate the association of enhanced E2F1 activity with aggressive phenotype, we performed a gene-specific silencing approach in a metastatic melanoma model. Knockdown of endogenous E2F1 via E2F1 small hairpin RNA (shRNA) expression increased E-cadherin expression of metastatic SK-Mel-147 melanoma cells and reduced their invasive potential but not their proliferative activity. Although growth rates of SK-Mel-147 and SK-Mel-103 xenograft tumors expressing E2F1 shRNA or control shRNA were similar, mice implanted with cells expressing E2F1 shRNA had a smaller area of metastases per lung than control mice (n = 3 mice per group; 5% vs 46%, difference = 41%, 95% confidence interval = 15% to 67%; P = .01; one-way analysis of variance). We identified epidermal growth factor receptor as a direct target of E2F1 and demonstrated that inhibition of receptor signaling abrogates E2F1-induced invasiveness, emphasizing the importance of the E2F1-epidermal growth factor receptor interaction as a driving force in melanoma progression that may serve as a paradigm for E2F1-induced metastasis in other human cancers.
authors.affiliation: Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Rostock, Germany.
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.forename: David
authors.initials: D
authors.lastname: Engelmann
authors.forename: Annett
authors.initials: A
authors.lastname: Niemetz
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Anke
authors.initials: A
authors.lastname: Schmidt
authors.forename: Manfred
authors.initials: M
authors.lastname: Kunz
authors.forename: Stephan
authors.initials: S
authors.lastname: Emmrich
authors.forename: Marc
authors.initials: M
authors.lastname: Steder
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000556:secondary*; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D066246:ErbB Receptors