Reduced expression of GNA11 and silencing of MCT1 in human breast cancers.
Alteration in the methylation status of a gene is often associated with its altered expression. Based on a genome scanning technique for differences in CpG methylations, methylation-sensitive representational difference analysis, DNA fragments hypermethylated in a human breast cancer were isolated. A DNA fragment was isolated from intron 1 of guanine-nucleotide-binding protein alpha-11 (GNA11). mRNA expression of GNA11 was shown to be decreased in 10 of 16 breast cancers by RT-PCR analysis, and the immunoreactivity of the GNA11 product, Galpha11 subunit of heterotrimeric G-protein, was observed to be reduced in 14 of the 16 cancers by immunohistochemistry. Methylation of a CpG island (CGI) in the 5' region of GNA11 or that of intron 1 did not show a clear correlation with its decreased expression. Another DNA fragment was isolated from a CGI in the 5' upstream region of monocarboxylate transporter 1 (MCT1), and was methylated in 4 of 20 breast cancers. The CGI was also methylated in a human breast cancer cell line, MDA-MB-231, and quantitative RT-PCR showed that its expression was almost lost in the cell line. By treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine, the methylation was removed and the expression was restored. GNA11 is involved in signalling of gonadotropin-releasing hormone receptor, which negatively regulates cell growth. MCT1 is involved in cellular transportation of butyrate, which induces cellular differentiation. Downregulation of these two genes was suggested to be involved in human breast cancers.
Asada
Kiyoshi
K
Division of Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan.
Miyamoto
Kazuaki
K
Fukutomi
Takashi
T
Tsuda
Hitoshi
H
Yagi
Yukiko
Y
Wakazono
Kuniko
K
Oishi
Shoko
S
Fukui
Hiroshi
H
Sugimura
Takashi
T
Ushijima
Toshikazu
T
D001693:Biological Transport, Active; D001943:Breast Neoplasms / Q000235:genetics*; D002087:Butyrates / Q000378:metabolism; D053938:DNA Fragmentation; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007438:Introns; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011966:Receptors, LHRH / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D027981:Symporters / Q000235:genetics*; D000099233:Monocarboxylate Transport Protein 1
D002087:Butyrates; D004273:DNA, Neoplasm; D019204:GTP-Binding Proteins; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011966:Receptors, LHRH; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1