Methylation-mediated downregulation of the B-cell translocation gene 3 (BTG3) in breast cancer cells.
The incidence of solid tumors is low in individuals with Down syndrome (trisomy 21), suggesting the presence of one or more tumor suppressor genes on chromosome 21. Consistent with this finding, previous work has demonstrated frequent loss of heterozygosity (LOH) of a small (< 5 Mb) region of chromosome 21, particularly in breast cancer, indicating that a tumor suppressor gene(s) may be located in this region. We investigated the expression of BTG3, a gene in the LOH region on chromosome 21, in breast cancer cell lines. BTG3 has been shown to be a negative regulator of SRC tyrosine kinase, and BTG3 is a target of p53 and inhibits the activity of the E2F1 transcription factor. Here we demonstrate that in a wide variety of human breast cancer cell lines, BTG3 expression is markedly reduced in the absence of detectable mutations in the BTG3 promoter and coding region. In these cell lines, the promoter region of the BTG3 gene is hypermethylated when compared to normal breast cell lines. BTG3 gene expression can be restored by treatment with 5'-aza-deoxycytidine, an inhibitor of DNA methylation. These data support the hypothesis that BTG3 may act to suppress tumorigenesis and that hypermethylation is an important mechanism for inactivation of BTG3 and perhaps other tumor suppressor genes. The findings are consistent with a role for an additional copy of BTG3 in the reduced incidence of breast cancer in individuals with Down syndrome.
Yu
Jingwei
J
Department of Laboratory Medicine, University of California, San Francisco, 185 Berry Street, Suite 290, San Francisco, CA 94107, USA. Jingwei.Yu@ucsfmedctr.org
Zhang
Yingsha
Y
Qi
Zhongxia
Z
Kurtycz
Daniel
D
Vacano
Guido
G
Patterson
David
D
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism
C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D011506:Proteins