Mutational analysis of the LMO4 gene, encoding a BRCA1-interacting protein, in breast carcinomas.
The LIM domain-only genes LMO1 and LMO2 are translocated in acute T cell leukemia (T-ALL) and have been shown to be oncogenes in T lymphoid cells. LMO4, the fourth member of this family, is overexpressed in more than 50% of sporadic breast cancers, suggesting a role in breast oncogenesis. We recently found that LMO4 interacts with the breast/ovarian tumor suppressor BRCA1 and that LMO4 can repress its transcriptional activity. Since proto-oncogene deregulation can result from activating mutations in their coding or regulatory sequences, we explored whether the LMO4 gene undergoes somatic mutagenesis in breast cancer. Mutation analysis of the coding and 3' untranslated regions of the LMO4 gene was performed on 82 primary breast and 22 tumor cell lines. A somatic mutation was detected in one primary breast cancer, at the 3' end of exon 2, but was not present in normal DNA derived from the same patient. This mutation causes a frame-shift and potentially results in a truncated LMO4 polypeptide, LIM1(mut), lacking the second LIM domain. This mutant protein could still bind Ldb1 but no longer associated with CtIP or BRCA1. Our results show that somatic mutations within the LMO4 gene do occur in breast cancer but at a very low frequency. Thus, the primary mechanism by which LMO4 is deregulated in breast cancers appears to reflect overexpression of the gene rather than the acquisition of activating genetic mutations.
Sutherland
Kate D
KD
The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Parkville, Australia.
Visvader
Jane E
JE
Choong
David Y H
DY
Sum
Eleanor Y M
EY
Lindeman
Geoffrey J
GJ
Campbell
Ian G
IG
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060588:LIM Domain Proteins; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D002352:Carrier Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C486312:LDB1 protein, human; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; C491976:Lmo4 protein, mouse; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human