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Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer.

ABSTRACT: BACKGROUND: Cancer cell differentiation is an important characteristic of malignant tumor and has a great impact on prognosis and therapeutic decision for patients. The N-myc downstream regulated gene 1 (NDRG1), a putative tumor suppression gene, is involved in the regulation of human cell differentiation and metastasis in various cancers. Changes in the status of methylation of the NDRG1 gene have not been studied in detail in human breast cancer. RESULTS: The MDA-MB-231 breast tumor cell line could express NDRG1. However, it was only expressed after treatment with 5-Aza-2'-deoxycytidine (AZA) in T47D cell line, which revealed that NDRG1 expression could modulated by DNA methylation. Therefore, the fragment surrounding the transcript start site of NDRG1 gene promoter was cloned after sodium bisulfite DNA treatment. A high density (66%) of methylation for human NDRG1 gene promoter was detected in T47D; however, there was only 16% of methylated CpG dinucleotides in the NDRG1 gene promoter in MDA-MB-231. DNA methylation in the NDRG1 promoter was detected in 31.1% of primary breast cancer samples. Furthermore, the NDRG1 promoter methylation correlated with the Tumor Node Metastasis (TNM) at stage III/IV, metastasis, lymph invasion, moderate and poor histological grade in the breast cancer patients. CONCLUSION: These findings suggest that the DNA methylation status of NDRG1 gene may play an important role in the pathogenesis and/or development of breast cancer, and the expression could be regulated by aberrant DNA methylation.

SUBMITTER: Han LL

PROVIDER: S-EPMC3751627 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer.

Han Lin-Lin LL Hou Lin L Zhou Ming-Jin MJ Ma Zhong-liang ZL Lin Dong-Liang DL Wu Li L Ge Yin-lin YL

Journal of biomedical science 20130730

<h4>Background</h4>Cancer cell differentiation is an important characteristic of malignant tumor and has a great impact on prognosis and therapeutic decision for patients. The N-myc downstream regulated gene 1 (NDRG1), a putative tumor suppression gene, is involved in the regulation of human cell differentiation and metastasis in various cancers. Changes in the status of methylation of the NDRG1 gene have not been studied in detail in human breast cancer.<h4>Results</h4>The MDA-MB-231 breast tum ...[more]

PMID: 23899187

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Project description:Aberrant expression of the transcription factor hematopoietic ally expressed homeobox/proline-rich homeodomain (HHEX/PRH) is implicated in numerous cancers. However, the association of HHEX with breast cancer (BC) remains unclear. In this study, HHEX mRNA and protein expression were analyzed using the Oncomine, UALCAN, GEPIA, TCGAportal, and HPA databases. We evaluated the effect of HHEX on clinicopathological parameters using Kaplan-Meier plotter, OncoLnc, TCGAportal, PROGgeneV2, and BC-GenExMiner. Western blotting was performed to compare the level of HHEX in breast samples of Tientsin Albino 2 mice, human breast precancerous lesions, benign breast tumors, and BC. The correlation between HHEX and cancer stem cells was investigated using the GEO (GSE52327 and GSE94865) and GEPIA datasets. Networks between HHEX and survival-related gene marker sets and microRNAs were analyzed using GEPIA, StarBase, and Cytoscape. Results of this study showed that HHEX expression in BC was significantly lower than those in breast precancerous lesions and benign breast tumors at both mRNA and protein levels. BC patients with lower HHEX expression had significantly worse overall survival and disease-free survival. Moreover, HHEX significantly affected the clinicopathology of BC. Specifically, low HHEX expression was correlated with the following groups of patients: age ≤51 years, ER-negative or PR-negative patients, HER-2 positive, triple-negative breast cancer, and basal-like BC. Immunohistochemical analysis of the breast samples showed significant differences of HHEX staining index (P < 0.001) among the three groups. To further investigate the mechanism, we determined the intersection of differentially expressed genes related to BC stem cells and those genes after HHEX expression was altered. This led to the identification of four potentially regulated genes-CXL12, BLNK, PAG1, and LPXN. Using StarBase and km-plotter, the negative regulation of HHEX expression and survival trends, including miR-130b, miR-30e, and miR-301b were joined into miRNA-HHEX-mRNA potential regulatory network. The abilities of proliferation, migration and invasion increased in MDA-MB-231 and BT-549 breast cancer cell lines after HHEX down expression and decreased after HHEX overexpression compared them in the control cells. In conclusion, these data suggest that HHEX expression is downregulated in BC and HHEX may regulate the development of BC through the stem cell-related genes.

Dataset Information

Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer.

Publications

Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer.

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