Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression.
The differentiation-related gene-1 (Drg-1) was first identified as a gene strongly upregulated by induction of differentiation in colon carcinoma cells in vitro, and later the same gene was shown to suppress tumorigenicity of human bladder cancer cells in vivo. On the other hand, we and others have demonstrated that the Drg-1 gene suppresses prostate and colon cancer metastases in mouse models. In the context of such potential organ-specific differential function of the Drg-1 gene, the present study was designed to clarify the expression status, regulation and function of Drg-1 in the case of human breast cancer. We found that the expression of the Drg-1 protein was significantly reduced in breast tumor cells, particularly in patients with lymph node or bone metastasis as compared to those with localized breast cancer. Drg-1 expression also exhibited significant inverse correlation with the disease-free survival rate of patients and emerged as an independent prognostic factor. The downregulation of the Drg-1 gene appeared to be largely at the RNA level, and the DNA methylation inhibitor, 5-Azacytidine, significantly elevated the Drg-1 gene expression in various breast tumor cell lines. Furthermore, we found that overexpression of the Drg-1 gene suppresses the invasiveness of breast cancer cells in vitro, and this suppression was also achieved by treatment of cells with 5-Azacytidine. Together, our results strongly suggest functional involvement of the Drg-1 gene in suppressing the metastatic advancement of human breast cancer.
Bandyopadhyay
Sucharita
S
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA.
Pai
Sudha K
SK
Hirota
Shigeru
S
Hosobe
Sadahiro
S
Takano
Yukio
Y
Saito
Ken
K
Piquemal
David
D
Commes
Therese
T
Watabe
Misako
M
Gross
Steven C
SC
Wang
Ying
Y
Ran
Sophia
S
Watabe
Kounosuke
K
D001943:Breast Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C078418:developmentally regulated GTP-binding protein; D019204:GTP-Binding Proteins