title: ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer.
abstract: Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer.
authors.affiliation: Department of Urology and Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Department of Systems Biology, and Department of Medicine and Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Aytes
authors.forename: Antonina
authors.initials: A
authors.lastname: Mitrofanova
authors.forename: Carolyn Waugh
authors.initials: CW
authors.lastname: Kinkade
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Vanessa
authors.initials: V
authors.lastname: Phelan
authors.forename: H Carl
authors.initials: HC
authors.lastname: LeKaye
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shen
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D005818:Genetic Engineering; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017500:Adenovirus E1A Proteins; C079853:ETV4 protein, human; C540571:Etv4 protein, mouse; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D018631:ras Proteins
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