Aberrant Vimentin Methylation Is Characteristic of Breast Cancer

Abstract

Background: Epigenetic mechanisms including DNA methylation are key regulators of gene activity and may play key roles in carcinogenesis through cumulative activation and inactivation of oncogenes, tumor suppressor genes, and other genes. Increased vimentin gene expression has been reported in various tumor cell lines and tissues including breast cancer. In addition, methylation of the vimentin gene was described as a marker in several malignant tumors. Objective: The aim of this study is to determine the existence of a potential relationship between the methylation state of the vimentin gene and its prognostic value in breast cancer patients and its correlation with vimentin protein expression in the serum. Patients and Methods: The methylation status of the vimentin gene was examined in primary infiltrating ductaltumors and the surrounding normal tissues derived from 50 breast cancer patients enrolled for either modified radical mastectomy or conservative breast surgery using quantitative methylation-specific polymerase chain reaction (qMSP), serum vimentin levels were determined using ELISA, and the correlation between the methylation status and the clinicopathological findings was evaluated. Results: Out of 50 breast cancer patients, 18 (36%) exhibited positive methylation of vimentin gene while 32 (64%) exhibited negative vimentin genemethylation in their tumors. Subsequently clinicopathological data were correlated with the vimentin genemethylation score. A significant association was found between negative vimentin methylation, and both serum vimentin protein level (p < 0.001) and the triple negative breast cancer subtype (TNBCs) (p = 0.004). Using receiver-operating characteristic (ROC) curve analysis, a cut off value of <0.49 was set for the negative vimentin methylation score to distinguish between early and late stage breast cancer, and the ROC curve showed an area under the curve (AUC) of 0.684 (p = 0.029). Conclusion: Our study showed that the vimentin gene is frequently hypomethylated in breast cancer tissues, and that 151negative methylation status is always associated with high serum vimentin protein expression levels. Also we reported a significant association between negative vimentin methylation and TNBC subtype which is known to have an aggressive clinical course. Taken together, these results might have important implications for the design of novel therapeutic interventions for breast cancer patients. However, further studies with larger sample size are needed to validate these observations.

Aspects of the Epigenetic Regulation of EMT Related to Cancer Metastasis

“…VIM may be used for the early detection of several cancers and hypermethylation of the promoter is important for the transcriptional silencing of the gene in cancer cells [ 32 ]. On the other hand, increased levels of vimentin in the serum may be caused by hypomethylation of the vimentin gene and increased expression of the vimentin gene intracellularly, leading to secretion of high levels of soluble vimentin in the serum [ 34 ]. Additionally, varying degrees of methylation within a gene’s CpG islands leads to various levels of gene silencing, and DNA methylation is considered as an epigenetic biomarker for cancer detection [ 47 ].…”

“…promoter hypomethylation colon adenocarcinoma [30] OCLN downregulation corelated with increase in miR-122 and miR-34a expression clear cell renal carcinoma [31] VIM promoter hypermethylation cervical cancer cells [32] DNA methylation (detected in the serum) colorectal cancer at every disease stage [33] low methylation associated with elevated vimentin protein level in the serum breast cancer [34] 3.1. Epigenetic Changes of Genes Mediating Cell Adhesion, Migration, and Motility…”

Proteomics-Based Identification of Dysregulated Proteins and Biomarker Discovery in Invasive Ductal Carcinoma, the Most Common Breast Cancer Subtype

“…Vimentin (VIM), a protein used as a mesenchymal biomarker that acts as a central player in EMT processes, was detected via MALDI-ToF/ToF MS to be overexpressed in IDC PBT compared to its low levels in matched lymph node metastases (LNM) [ 80 ], in IDC compared with ILC samples [ 84 ], as well as in fresh frozen (FF) breast tissue biopsies of ER+/HER2/ neu negative IDC, using LC–MS E and MALDI-MS/MS [ 23 ]. Vimentin was also detected at high levels in the sera of patients with IDC, where the vimentin gene was also found to be hypomethylated [ 153 ]. MALDI-ToF MS also quantified a vimentin DNA methylation process in breast tumors and matched control pairs [ 154 ].…”