Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression

Abstract

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.

Metastasis-related Plasma Membrane Proteins of Human Breast Cancer Cells Identified by Comparative Quantitative Mass Spectrometry

“…The function of this protein remains unclear, and some controversy regarding its role in cancer exists. Some studies suggest NDRG1 involvement in metastatic suppression, whereas others show higher expression of this protein, likely related to metastasis (51)(52)(53)(54)(55). The difference in subcellular localization of NDRG1 may be important for its function, and we therefore remain open to the concept that it plays some role in the development of metastases.…”

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

“…In addition, NDRG1 was found to be negatively correlated with tumor progression, while being positively correlated with better patient prognosis for a range of cancers, including those of the prostate, breast, colon, and pancreas (5,(11)(12)(13)16). Considering the potential therapeutic implications of utilizing NDRG1 as a molecular target for the treatment of cancer, the molecular mechanisms by which NDRG1 is able to exert its anti-cancer effects have recently become the subject of intense research.…”

“…In fact, studies examining the prognosis of patients with these latter neoplasms demonstrated that those with higher NDRG1 levels had a significantly better outcome when compared with those with low NDRG1 levels (5,(11)(12)(13). Hence, NDRG1 is a promising prognostic indicator and molecular target for these cancers (14), which represent some of the most common and fatal neoplastic conditions.…”

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

“…Overexpression of NDRG1 in vitro results in morphological changes typical of cell differentiation and is inversely related to tumour growth and metastasis (Kurdistani et al, 1998;Guan et al, 2000;Bandyopadhyay et al, 2003;Bandyopadhyay et al, 2004a). Furthermore, its expression is increased by the tumour suppressor proteins p53 and PTEN (Kurdistani et al, 1998;Bandyopadhyay et al, 2004b) and clinical data have shown that its presence is statistically correlated with an increased survival of patients diagnosed with prostate cancer or liver metastasis from colorectal cancers (Bandyopadhyay et al, 2003;Shah et al, 2005).…”