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Article: A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention

TitleA Genetic Progression Model of Braf<sup>V600E</sup>-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention
Authors
Issue Date2013
Citation
Cancer Cell, 2013, v. 24, n. 1, p. 15-29 How to Cite?
AbstractWe show that BRAF V600E initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf V600E expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition. © 2013 Elsevier Inc.
Persistent Identifierhttp://hdl.handle.net/10722/249076
ISSN
2017 Impact Factor: 22.844
2015 SCImago Journal Rankings: 13.922
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRad, Roland-
dc.contributor.authorCadiñanos, Juan-
dc.contributor.authorRad, Lena-
dc.contributor.authorVarela, Ignacio-
dc.contributor.authorStrong, Alexander-
dc.contributor.authorKriegl, Lydia-
dc.contributor.authorConstantino-Casas, Fernando-
dc.contributor.authorEser, Stefan-
dc.contributor.authorHieber, Maren-
dc.contributor.authorSeidler, Barbara-
dc.contributor.authorPrice, Stacey-
dc.contributor.authorFraga, Mario F.-
dc.contributor.authorCalvanese, Vincenzo-
dc.contributor.authorHoffman, Gary-
dc.contributor.authorPonstingl, Hannes-
dc.contributor.authorSchneider, Günter-
dc.contributor.authorYusa, Kosuke-
dc.contributor.authorGrove, Carolyn-
dc.contributor.authorSchmid, Roland M.-
dc.contributor.authorWang, Wei-
dc.contributor.authorVassiliou, George-
dc.contributor.authorKirchner, Thomas-
dc.contributor.authorMcDermott, Ultan-
dc.contributor.authorLiu, Pentao-
dc.contributor.authorSaur, Dieter-
dc.contributor.authorBradley, Allan-
dc.date.accessioned2017-10-27T05:59:02Z-
dc.date.available2017-10-27T05:59:02Z-
dc.date.issued2013-
dc.identifier.citationCancer Cell, 2013, v. 24, n. 1, p. 15-29-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/249076-
dc.description.abstractWe show that BRAF V600E initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf V600E expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition. © 2013 Elsevier Inc.-
dc.languageeng-
dc.relation.ispartofCancer Cell-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleA Genetic Progression Model of Braf<sup>V600E</sup>-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ccr.2013.05.014-
dc.identifier.pmid23845441-
dc.identifier.scopuseid_2-s2.0-84880020762-
dc.identifier.volume24-
dc.identifier.issue1-
dc.identifier.spage15-
dc.identifier.epage29-
dc.identifier.eissn1878-3686-
dc.identifier.isiWOS:000321604000007-
dc.identifier.f1000718029904-

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