Activation of antimetastatic Nm23-H1 gene expression by estrogen and its alpha-receptor.
Metastasis of various malignant cells is inversely related to the abundance of the Nm23-H1 protein. The role of estrogens in tumor metastasis has now been investigated by examining the effect of E2 on the expression of the Nm23-H1 gene. Three human breast carcinoma cell lines, in which endogenous ERalpha is expressed at different levels, were used as a tool to assess the role of ERalpha in Nm23-H1 gene-mediated metastasis. E2 induced time-dependent increases in the abundance of Nm23-H1 mRNA and protein, with the extent of these effects correlating with the level of expression of ERalpha. E2 induced a marked decrease in the invasive activity of MCF-7 and BT-474 cells but had no effect on BCM-1 cells, which had virtually no ERalpha. Consistent with these results, the ER-mediated Nm23-H1 promoter activity was inhibited 3-fold by the E2 antagonist, ICI 182,780. Deletion analysis of the promoter region of the Nm23-H1 gene identified a positive estrogen-responsive element located in -108/-94. ER protein bound specifically to the -108/-79 fragment with high avidity. These results indicate that E2, acting through ERalpha, activated transcription of the Nm23-H1 gene via a positive estrogen-responsive element in the promoter region of the gene. These results suggest that E2 could suppress tumor metastasis by activating the expression of the Nm23-H1 gene.
Lin
Kwang-Huei
KH
Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan, Republic of China. khlin@mail2000.com.tw
Wang
Won-Jing
WJ
Wu
Yi-Hsin
YH
Cheng
Sheue-Yann
SY
D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000235:genetics* / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D054778:NM23 Nucleoside Diphosphate Kinases; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D009701:Nucleoside-Diphosphate Kinase; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics* / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D004967:Estrogens; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D014157:Transcription Factors; D004958:Estradiol; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020559:Monomeric GTP-Binding Proteins