Characterization of KRAS rearrangements in metastatic prostate cancer.
Cancer Discov
; 1(1): 35-43, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-22140652
ABSTRACT
UNLABELLED Using an integrative genomics approach called amplification breakpoint ranking and assembly analysis, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line, originally derived from prostate cancer metastasis to the brain. Interestingly, analysis of tissues revealed that 2 of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion protein, a specific knockdown of which attenuates cell invasion and xenograft growth. Ectopic expression of the UBE2L3-KRAS fusion protein exhibits transforming activity in NIH 3T3 fibroblasts and RWPE prostate epithelial cells in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates MEK/ERK signaling, commonly engaged by oncogenic mutant KRAS, and instead signals via AKT and p38 mitogen-activated protein kinase (MAPK) pathways. This is the first report of a gene fusion involving the Ras family, suggesting that this aberration may drive metastatic progression in a rare subset of prostate cancers. SIGNIFICANCE:
This is the first description of an oncogenic gene fusion of KRAS, one of the most studied proto-oncogenes. KRAS rearrangement may represent the driving mutation in a rare subset of metastatic prostate cancers, emphasizing the importance of RAS-RAF-MAPK signaling in this disease.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Rearranjo Gênico
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Proteínas Proto-Oncogênicas p21(ras)
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Proteínas Proto-Oncogênicas
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Proteínas ras
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Discov
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos