IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34
Autor/es:
MARTIN C. ABBA; VICTORIA T. FABRIS; YUHUI HU; FRANCES S. KITTRELL; WEI-WEN CAI; LAWRENCE A. DONEHOWER; AYSEGUL SAHIN; DANIEL MEDINA; C. MARCELO ALDAZ
Revista:
CANCER RESEARCH
Referencias:
Año: 2007 vol. 67 p. 4104 - 4112
ISSN:
0008-5472
Resumen:
Serial analysis of gene expression from aggressive mammary
tumors derived from transplantable p53 null mouse mammary
outgrowth lines revealed significant up-regulation of Tfdp1
(transcription factor Dp1), Lamp1 (lysosomal membrane
glycoprotein 1) and Gas6 (growth arrest specific 6) transcripts.
All of these genes belong to the same linkage cluster, mapping
to mouse chromosome band 8A1. BAC-array comparative
genomic hybridization and fluorescence in situ hybridization
analyses revealed genomic amplification at mouse region
ch8A1.1. The minimal region of amplification contained genes
Cul4a, Lamp1, Tfdp1, and Gas6, highly overexpressed in the
p53 null mammary outgrowth lines at preneoplastic stages,
and in all its derived tumors. The same amplification was also
observed in spontaneous p53 null mammary tumors. Interestingly,
this region is homologous to human chromosome
13q34, and some of the same genes were previously observed
amplified in human carcinomas. Thus, we further investigated
the occurrence and frequency of gene amplification affecting
genes mapping to ch13q34 in human breast cancer. TFDP1
showed the highest frequency of amplification affecting 31% of
74 breast carcinomas analyzed. Statistically significant positive
correlation was observed for the amplification of CUL4A,
LAMP1, TFDP1, and GAS6 genes (P < 0.001). Meta-analysis of
publicly available gene expression data sets showed a strong
association between the high expression of TFDP1 and
decreased overall survival (P = 0.00004), relapse-free survival
(P = 0.0119), and metastasis-free interval (P = 0.0064). In
conclusion, our findings suggest that CUL4A, LAMP1, TFDP1,
and GAS6 are targets for overexpression and amplification in
breast cancers. Therefore, overexpression of these genes and,
in particular, TFDP1 might be of relevance in the development
and/or progression in a significant subset of human breast
carcinomas.