Back
 ABCR  Vol.5 No.4 , October 2016
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 negative 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.
Cite this paper: Dwedar, F. , Khalil, G. , Nayer, S. and Farouk, A. (2016) Aberrant Vimentin Methylation Is Characteristic of Breast Cancer. Advances in Breast Cancer Research, 5, 150-162. doi: 10.4236/abcr.2016.54018.
References

[1]   Cancer Genome Atlas Network (2012) Comprehensive Molecular Portraits of Human Breast Tumours. Nature, 490, 61-70.
http://dx.doi.org/10.1038/nature11412

[2]   Ibrahim, A.S., Khaled, H.M., Mikhail, N.N.H., Baraka, H. and Kamel, H. (2014) Cancer Incidence in Egypt: Results of the National Population-Based Cancer Registry Program. Journal of Cancer Epidemiology, 2014, Article ID: 437971.
http://dx.doi.org/10.1155/2014/437971

[3]   Karina, B., Hirata, B., Oda, J.M.M., Guembarovski, R.L., Ariza, C.B., de Oliveira, C.E.C. and Watanabe, M.A.E. (2014) Molecular Markers for Breast Cancer: Prediction on Tumor Behavior. Disease Markers, 2014, Article ID: 513158.
http://dx.doi.org/10.1155/2014/513158

[4]   Jung, S., Yi, L.S., Kim, J.S., Jeong, D.J., Oh, T., Kim, C.-H., Kim, C.-J., Shin, J., An, S. and Lee, M.-S. (2011) The Role of Vimentin as a Methylation Biomarker for Early Diagnosis of Cervical Cancer. Molecules and Cells, 31, 405-411.

[5]   Fleischer, T., Frigessi, A., Johnson, K.C., et al. (2014) Genome-Wide DNA Methylation Profiles in Progression to in Situ and Invasive Carcinoma of the Breast with Impact on Gene Transcription and Prognosis. Genome Biology, 15, 435.

[6]   Fleischer, T., Edvardsen, H., Solvang, H.K., et al. (2014) Integrated Analysis of High-Resolution DNA Methylation Profiles, Gene Expression, Germline Genotypes and Clinical End Points in Breast Cancer Patients. International Journal of Cancer, 134, 2615-2625.
http://dx.doi.org/10.1002/ijc.28606

[7]   Jovanovic, J., Ronneberg, J.A., Tost, J., et al. (2010) The Epigenetics of Breast Cancer. Molecular Oncology, 4, 242-254.
http://dx.doi.org/10.1016/j.molonc.2010.04.002

[8]   Kallerg, G., Papadak, M.A., Politaki, E., Mavroudis, D., Georgoulias, V. and Agelaki, S. (2011) Epithelial to Mesenchymal Transition Markers Expressed in Circulating Tumour Cells of Early and Metastatic Breast Cancer Patients. Breast Cancer Research, 13, 59.
http://dx.doi.org/10.1186/bcr2896

[9]   Ulirsch, J., Fan, C., Knafl, G., Wu, M.J., Coleman, B., Perou, C.M. and Swift-Scanlan, T. (2013) Vimentin DNA Methylation Predicts Survival in Breast Cancer. Breast Cancer Research and Treatment, 137, 383-396.
http://dx.doi.org/10.1007/s10549-012-2353-5

[10]   Fackler, M.J., Umbricht, C.B., Williams, D., Argani, P., Cruz, L.A., Merino, V.F., Teo, W.W., Zhang, Z., Huang, P., Visvananthan, K., Marks, J., Ethier, S., Gray, J.W., Wolff, A.C., Cope, L.M. and Sukumar, S. (2011) Genome-Wide Methylation Analysis Identifies Genes Specific to Breast Cancer Hormone Receptor Status and Risk of Recurrence. Cancer Research, 71, 6195-6207.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1630

[11]   Itzkowitz, S.H., Jandorf, L., Brand, R., Rabeneck, L., Schroy, P.C., Sontag, S., Johnson, D., Skoletsky, J., Durkee, K., Markowitz, S. and Shuber, A. (2007) Improved Fecal DNA Test for Colorectal Cancer Screening. Clinical Gastroenterology and Hepatology, 5, 111-117.
http://dx.doi.org/10.1016/j.cgh.2006.10.006

[12]   Kitamura, Y.H., Shirahata, A., Sakata, M., Goto, T., Mizukami, H., Saito, M., Ishibashi, K., Kigawa, G., Nemoto, H., Sanada, Y. and Hibi, K. (2009) Frequent Methylation of Vimentin in Well-Differentiated Gastric Carcinoma. Anticancer Research, 29, 2227-2229.

[13]   Costa, V.L., Henrique, R., Danielsen, S.A., Duarte-Pereira, S., Eknaes, M., Skotheim, R.I., Rodrigues, A., Magalhaes, J.S., Oliveira, J., Lothe, R.A., Teixeira, M.R., Jeronimo, C. and Lind, G.E. (2010) Three Epigenetic Biomarkers, GDF15, TMEFF2, and, VIM, Accurately Predict Bladder Cancer from DNA-Based Analyses of Urine Samples. Clinical Cancer Research, 16, 5842-5851.
http://dx.doi.org/10.1158/1078-0432.CCR-10-1312

[14]   Zhou, Y.F., Xu, W., Wang, X., Sun, J.S., Xiang, J.J., Li, Z.S. and Zhang, X.F. (2014) Negative Methylation Status of Vimentin Predicts Improved Prognosis in Pancreatic Carcinoma. World Journal of Gastroenterology, 20, 13172-13177.
http://dx.doi.org/10.3748/wjg.v20.i36.13172

[15]   Edge, S.B. (2010) Breast. In: Edge, S.B., Byrd, D.R. and Compton, C.C., Eds., AJCC Cancer Staging Manual, 7th Edition, Springer, New York, 347-376.

[16]   Tokunaga, E., Kimura, Y., Oki, E., Ueda, N., Futatsugi, M., Mashino, K., Yamamoto, M., Ikebe, M., Kakeji, Y., Baba, H. and Maehara, Y. (2006) Akt Is Frequently Activated in HER2/Neu-Positive Breast Cancers and Associated with Poor Prognosis among Hormone-Treated Patients. International Journal of Cancer, 118, 284-289.
http://dx.doi.org/10.1002/ijc.21358

[17]   Wong, I.H., Lo, Y.M., Zhang, J., Liew, C.T., Ng, M.H., Wong, N., et al. (1999) Detection of Aberrant P16 Methylation in the Plasma and Serum of Liver Cancer Patients. Cancer Research, 59, 71-73.

[18]   Tiwari, S.K., Manoj, G., Prasanth, K., Sivaram, G., Sharma, V.K., Habeeb, M.A., et al. (2009) Simplified and Versatile Method for Bisulfite-Based DNA Methylation Analysis of Small Amounts of DNA. Journal of Clinical Laboratory Analysis, 23, 172-174.
http://dx.doi.org/10.1002/jcla.20314

[19]   Kitamura, Y., Shirahata, A., Sakuraba, K., Goto, T., Mizukami, H., Saito, M., et al. (2011) Aberrant Methylation of the Vimentin Gene in Hepatocellular Carcinoma. Anticancer Research, 31, 1289-1291.

[20]   Moinova, H., Leidner, R.S., Ravi, L., Lutterbaugh, J., Barnholtz-Sloan, J.S., Chen, Y., Chak, A., Markowitz, S.D. and Willis, J.E. (2012) Aberrant Vimentin Methylation Is Characteristic of Upper Gastrointestinal Pathologies. Cancer Epidemiology Biomarkers & Prevention, 21, 594-600.
http://dx.doi.org/10.1158/1055-9965.EPI-11-1060

[21]   Shirahata, A., Sakata, M., Sakuraba, K., Goto, T., Mizukami, H., Saito, M., Ishibashi, K., Kigawa, G., Nemoto, H. and Sanada, Y. (2009) Vimentin Methylation as a Marker for Advanced Colorectal Carcinoma. Anticancer Research, 29, 279-281.

[22]   Wong, K.F. and Luk, J.M. (2012) Discovery of Lamin b1 and Vimentin as Circulating Biomarkers for Early Hepatocellular Carcinoma. Methods in Molecular Biology, 909, 295-310.

[23]   Rybarova, S., Vecanova, J., Hodorova, I., et al. (2011) Association between Polymorphisms of XRCC1, p53 and MDR1 Genes, the Expression of Their Protein Products and Prognostic Significance in Human Breast Cancer. Medical Science Monitor, 17, 354-363.
http://dx.doi.org/10.12659/MSM.882121

[24]   Tvrdik, D., Skalova, H., Dundr, P., et al. (2012) Apoptosis—Associated Genes and Their Role in Predicting Responses to Neoadjuvant Breast Cancer Treatment. Medical Science Monitor, 18, 60-67.
http://dx.doi.org/10.12659/MSM.882205

[25]   Liu, Y., Zhao, J., Zhang, P., Zhang, Y., Sun, S., Yu, S. and Xi, Q. (2012) MicroRNA-10b Targets E-Cadherin and Modulates Breast Cancer Metastasis. Medical Science Monitor, 18, 299-308.
http://dx.doi.org/10.12659/MSM.883262

[26]   Satelli, A. and Li, S. (2011) Vimentin as a Potential Molecular Target in Cancer Therapy or Vimentin, an Overview and Its Potential as a Molecular Target for Cancer Therapy. Cellular and Molecular Life Sciences, 68, 3033-3046.
http://dx.doi.org/10.1007/s00018-011-0735-1

[27]   Gyorffy, B., Bottai, G., Fleischer, T., Munkacsy, G., Budczies, J., Paladini, L., et al. (2016) Aberrant DNA Methylation Impacts Gene Expression and Prognosis in Breast Cancer Subtypes. International Journal of Cancer, 138, 87-97.
http://dx.doi.org/10.1002/ijc.29684

[28]   Yamashita, N., Tokunaga, E., Kitao, H., Hisamatsu, Y., Taketani, K., Akiyoshi, S., et al. (2013) Vimentin as a Poor Prognostic Factor for Triple-Negative Breast Cancer. Journal of Cancer Research and Clinical Oncology, 139, 739-746.
http://dx.doi.org/10.1007/s00432-013-1376-6

[29]   Karihtala, P., Auvinen, P., Kauppila, S., Haapasaari, K.M., Jukkola-Vuorinen, A. and Soini, Y. (2013) Vimentin, Zeb1 and Sip1 Are Up-Regulated in Triple-Negative and Basal-Like Breast Cancers: Association with an Aggressive Tumour Phenotype. Breast Cancer Research and Treatment, 138, 81-90.
http://dx.doi.org/10.1007/s10549-013-2442-0

[30]   Mor-Vaknin, N., Sitwala, K. and Markovitz, D.M. (2003) Vimentin Is Secreted by Activated Macrophages. Nature Cell Biology, 5, 59-63.
http://dx.doi.org/10.1038/ncb898

[31]   Kallergi, G., Politaki, E., Mavroudis, D., Georgoulias, V. and Agelaki, S. (2011) Epithelial to Mesenchymal Transition Markers Expressed in Circulating Tumor Cells of Early and Metastatic Breast Cancer Patients. Breast Cancer Research, 13, R59.
http://dx.doi.org/10.1186/bcr2896

[32]   Chaffer, C.L., Brennan, J.P., Slavin, J.L., Blick, T., Thompson, E.W. and Williams, E.D. (2006) Mesenchymal-to-Epithelial Transition Facilitates Bladder Cancer Metastasis: Role of Fibroblast Growth Factor Receptor-2. Cancer Research, 66, 11271-11278.
http://dx.doi.org/10.1158/0008-5472.CAN-06-2044

[33]   Gjerdrum, C., Tiron, C., Hoiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B.T., Micklem, D.R., Akslen, L.A., Glackin, C. and Lorens, J.B. (2010) Axl Is an Essential Epithelial-to-Mesenchymal Transition-Induced Regulator of Breast Cancer Metastasis and Patient Survival. Proceedings of the National Academy of Sciences of the United States of America, 107, 1124-1129.
http://dx.doi.org/10.1073/pnas.0909333107

[34]   Holland, S.J., Powell, M.J., Franci, C., Chan, E.W., Friera, A.M., Atchison, R.E., McLaughlin, J., Swift, S.E., Pali, E.S., Yam, G., Wong, S., Lasaga, J., Shen, M.R., Yu, S., Xu, W., Hitoshi, Y., Bogenberger, J., Nor, J.E., Payan, D.G. and Lorens, J.B. (2005) Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation. Cancer Research, 65, 9294-9303.
http://dx.doi.org/10.1158/0008-5472.CAN-05-0993

[35]   Fuyuhiro, Y., Yashiro, M., Noda, S., Kashiwagi, S., Matsuoka, J., Doi, Y., et al. (2010) Clinical Significance of Vimentin-Positive Gastric Cancer Cells. Anticancer Research, 30, 5239-5243.

[36]   Jin, H., Morohashi, S., Sato, F., Kudo, Y., Akasaka, H., Tsutsumi, S., et al. (2010) Vimentin Expression of Esophageal Squamous Cell Carcinoma and Its Aggressive Potential for Lymph Node Metastasis. BioMed Research, 31, 105-112.
http://dx.doi.org/10.2220/biomedres.31.105

[37]   Alfonso, P., Nunez, A., Madoz-Gurpide, J., Lombardia, L., Sanchez, L. and Casal, J.I. (2005) Proteomic Expression Analysis of Colorectal Cancer by Two-Dimensional Differential Gel Electrophoresis. Proteomics, 5, 2602-2611.
http://dx.doi.org/10.1002/pmic.200401196

[38]   McInroy, L. and Maatta, A. (2007) Down-Regulation of Vimentin Expression Inhibits Carcinoma Cell Migration and Adhesion. Biochemical and Biophysical Research Communications, 360, 109-114.
http://dx.doi.org/10.1016/j.bbrc.2007.06.036

[39]   Hong, S.H., Misek, D.E., Wang, H., Puravs, E., Hinderer, R., Giordano, T.J., et al. (2006) Identification of a Specific Vimentin Isoform That Induces an Antibody Response in Pancreatic Cancer. Biomarker Insights, 1, 175-183.

[40]   Walsh, N., O’Donovan, N., Kennedy, S., Henry, M., Meleady, P., Clynes, M., et al. (2009) Identification of Pancreatic Cancer Invasion-Related Proteins by Proteomic Analysis. Proteome Science, 7, 3.
http://dx.doi.org/10.1186/1477-5956-7-3

[41]   Korsching, E., Packeisen, J., Liedtke, C., Hungermann, D., Wulfing, P., van Diest, P.J., et al. (2005) The Origin of Vimentin Expression in Invasive Breast Cancer: Epithelial-Mesenchymal Transition, Myoepithelial Histogenesis or Histogenesis from Progenitor Cells with Bilinear Differentiation Potential. Journal of Pathology, 206, 451-457.
http://dx.doi.org/10.1002/path.1797

[42]   Li, M., Zhang, B., Sun, B., Wang, X., Ban, X., Sun, T., et al. (2010) A Novel Function for Vimentin: The Potential Biomarker for Predicting Melanoma Hematogenous Metastasis. Journal of Experimental and Clinical Cancer Research, 29, 109.
http://dx.doi.org/10.1186/1756-9966-29-109

[43]   Fortin, S., Le Mercier, M., Camby, I., Spiegl-Kreinecker, S., Berger, W., Lefranc, F., et al. (2010) Galectin-1 Is Implicated in the Protein Kinase C Epsilon/Vimentin-Controlled Trafficking of Integrin-Beta1 in Glioblastoma Cells. Brain Pathology, 20, 39-49.
http://dx.doi.org/10.1111/j.1750-3639.2008.00227.x

[44]   Li, Z.M., Wen, Y.J., Yang, H.B., Qin, G., Tian, L., Deng, H.X., et al. (2008) Enhanced Expression of Human Vimentin Intermediate Filaments in Hepatocellular Carcinoma Cells Decreases Their Proliferative and Invasive Abilities in Vitro. Chinese Journal of Oncology, 30, 408-412.

[45]   Bouamrani, A., Ramus, C., Gay, E., Pelletier, L., Cubizolles, M., Brugiere, S., et al. (2010) Increased Phosphorylation of Vimentin in Noninfiltrative Meningiomas. PLoS ONE, 5, e9238.
http://dx.doi.org/10.1371/journal.pone.0009238

[46]   Chen, W., Han, Z.J., Skoletsk, J., Olson, J., Sah, J., Myeroff, L., et al. (2005) Detection in Fecal DNA of Colon Cancer-Specific Methylation of the Nonexpressed Vimentin Gene. Journal of the National Cancer Institute, 97, 1124-1132.
http://dx.doi.org/10.1093/jnci/dji204

 
 
Top