Share This Article:

Homocysteine as a Biomarker for Predicting Disease-Free Survival in Breast Cancer

Full-Text HTML XML Download Download as PDF (Size:774KB) PP. 24-31
DOI: 10.4236/abcr.2013.22006    3,412 Downloads   6,825 Views   Citations

ABSTRACT

Introduction: Breast cancer is the leading cause of cancer mortality among women. Some biomarkers and clinical features are used for the diagnosis and prognosis of this tumor, but no prognostic or predictive marker is routinely available specifically for hormone receptor positive tumors. Homocysteine is well known as a risk factor in atherosclerotic vascular diseases, but its participation in cancer biology is still unclear. The aim of this study was to evaluate serum Homocysteine and Cysteine as biomarkers of disease progression in breast tumor. As a secondary objective, the effect of a short course (one month) of hormonal treatment on Homocysteine, Cysteine and DNA methylation levels was also evaluated. Methods: Blood samples, tumor samples and normal adjacent tissue were collected during the initial biopsy (pre-treatment) and after one month of hormonal therapy (post-treatment). Serum Homocysteine and Cysteine were analyzed by HPLC and tissue global DNA methylation was determined by the Methylation-Sensitive Restriction Enzyme (MSRE) technique. Results: Variations in Homocysteine levels were significantly correlated with Disease-Free Survival. Cox proportional risk model demonstrated that nodal status and Homocysteine levels were independent prognostic factors for disease-free survival (DFS). A significant difference was observed between pre-and post-treatment levels of Homocysteine and Cysteine in advanced tumors, suggesting a prognostic role in patients with poor clinical characteristics. Conclusion: Although more studies are needed to confirm these results, our research suggests that Hcy might be used as a prognostic biomarker for breast cancer.

Cite this paper

Ierardi, D. , Raimundo, L. , Aguiar, G. , Germano, P. , Gebrim, L. , Carvas, N. , Calegare, B. , D’Almeida, V. , Porto, C. , Jasiulionis, M. and Correa, M. (2013) Homocysteine as a Biomarker for Predicting Disease-Free Survival in Breast Cancer. Advances in Breast Cancer Research, 2, 24-31. doi: 10.4236/abcr.2013.22006.

References

[1] T. S. Foster, J. D. Miller, M. E. Boye, M. B. Blieden, R. Gidwani and M. W. Russell, “The Economic Burden of Metastatic Breast Cancer: A Systematic Review of Literature from Developed Countries,” Cancer Treatment Reviews, Vol. 37, No. 6, 2011, pp. 405-415.
[2] B. Metzger, L. Chambeau, D. Y. Begon, C. Faber, J. Kayser, G. Berchem, M. Pauly, J. Boniver, P. Delvenne, M. Dicato and T. Wenner, “The Human Epidermal Growth Factor Receptor (EGFR) Gene in European Patients with Advanced Colorectal Cancer Harbors Infrequent Mutations in Its Tyrosine Kinase Domain,” BMC Medical Genetics, Vol. 12, No. 1, 2011, p. 144. doi:10.1186/1471-2350-12-144
[3] S. R. Johnston, “New Strategies in Estrogen ReceptorPositive Breast Cancer,” Clinical Cancer Research, Vol. 16, No. 7, 2010, pp. 1979-1987. doi:10.1158/1078-0432.CCR-09-1823
[4] Early Breast Cancer Trialists Collaborative Group, “Tamoxifen for Early Breast Cancer: An Overview of the Randomised Trials. Early Breast Cancer Trialists’ Collaborative Group,” Lancet, Vol. 351, No. 9114, 1998, pp. 1451-1467. doi:10.1016/S0140-6736(97)11423-4
[5] I. H. Abdulkareem and I. B. Zurmi, “Review of Hormonal Treatment of Breast Cancer,” Nigerian Journal of Clinical Practice, Vol. 15, No. 1, 2012, pp. 9-14. doi:10.4103/1119-3077.94088
[6] K. Miyaki, “Genetic Polymorphisms in Homocysteine Metabolism and Response to Folate Intake: A Comprehensive Strategy to Elucidate Useful Genetic Information,” Journal of Epidemiology, Vol. 20, No. 4, 2010, pp. 266-270. doi:10.2188/jea.JE20100042
[7] B. T. Zhu, “On the Mechanism of Homocysteine Pathophysiology and Pathogenesis: A Unifying Hypothesis,” Histology and Histopathology, Vol. 17, No. 4, 2002, pp. 1283-1291.
[8] P. Yi, S. Melnyk, M. Pogribna, I. P. Pogribny, R. J. Hine and S. J. James, “Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation,” The Journal of Biological Chemistry, Vol. 275, No. 38, 2000, pp. 29318-29223. doi:10.1074/jbc.M002725200
[9] M. Esteller and G. Almouzni, “How Epigenetics Integrates Nuclear Functions. Workshop on Epigenetics and Chromatin: Transcriptional Regulation and Beyond,” EMBO Reports, Vol. 6, No. 7, 2005, pp. 624-628. doi:10.1038/sj.embor.7400456
[10] P. Sharma, R. D. Senthilkumar, V. Brahmachari, E. Sundaramoorthy, A. Mahajan, A. Sharma and S. Sengupta, “Mining Literature for a Comprehensive Pathway Analysis: A Case Study for Retrieval of Homocysteine Related Genes for Genetic and Epigenetic Studies,” Lipids in Health and Disease, Vol. 5, No. 1, 2006, p. 1. doi:10.1186/1476-511X-5-1
[11] C. M. Pfeiffer, D. L. Huff and E. W. Gunter, “Rapid and Accurate HPLC Assay for Plasma Total Homocysteine and Cysteine in a Clinical Laboratory Setting,” Clinical Chemistry, Vol. 45, No. 2, 1999, pp. 290-292.
[12] B. R. Kirkwood and J. A. C. Sterne, “Essential Medical Statistic,” Blackwell Publishing Limited, Oxford, 2006.
[13] D. G. Kleinbaum and M. Klein, “Statistics for Biology and Health. Survival Analysis, Series: Statistics for Biology and Health,” Springer, New York, 2005.
[14] M. Hatziapostolou and D. Iliopoulos, “Epigenetic Aberrations during Oncogenesis,” Cellular and Molecular Life Sciences, Vol. 68, No. 10, 2011, pp. 1681-1702. doi:10.1007/s00018-010-0624-z
[15] E. Lonn, S. Yusuf, M. J. Arnold, P. Sheridan, J. Pogue, M. Micks, M. J. McQueen, J. Probstfield, G. Fodor, C. Held and J. Genest Jr., “Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease,” The New England Journal of Medicine, Vol. 354, No. 15, 2006, pp. 1567-1577. doi:10.1056/NEJMoa060900
[16] L. L. Wu and J. T. Wu, “Hyperhomocysteinemia Is a Risk Factor for Cancer and a New Potential Tumor Marker,” Clinica Chimica Acta, Vol. 322, No. 1-2, 2002, pp. 21-28. doi:10.1016/S0009-8981(02)00174-2
[17] J. Lin, I. M. Lee, Y. Song, N. R. Cook, J. Selhub, J. E. Manson, J. E. Buring and S. M. Zhang, “Plasma Homocysteine and Cysteine and Risk of Breast Cancer in Women,” Cancer Research, Vol. 70, No. 6, 2010, 2010, pp. 2397-2405.
[18] M. Brooks, “Breast Cancer Screening and Biomarkers,” Methods in Molecular Biology, Vol. 472, 2009, pp. 307-321. doi:10.1007/978-1-60327-492-0_13
[19] T. Wright and A. McGechan, “Breast Cancer: New Technologies for Risk Assessment and Diagnosis,” Journal of Molecular Diagnostics, Vol. 7, No. 1, 2003, pp. 49-55.
[20] C. L. Corless, “Medicine. Personalized cancer diagnostics,” Science, Vol. 334, No. 6060, 2011, pp. 1217-1218. doi:10.1126/science.1216427
[21] M. H. Stipanuk, J. E. Dominy Jr., J. I. Lee and R. M. Coloso, “Mammalian Cysteine Metabolism: New Insights into Regulation of Cysteine Metabolism,” Journal of Nutrition, Vol. 136, Suppl. 6, 2006, pp. 1652S-1659S.
[22] J. Soares, A. E. Pinto, C. V. Cunha, S. Andre, I. Barao, J. M. Sousa and M. Cravo, “Global DNA Hypomethylation in Breast Carcinoma: Correlation with Prognostic Factors and Tumor Progression,” Cancer, Vol. 85, No. 1, 1999, pp. 112-118. doi:10.1002/(SICI)1097-0142(19990101)85:1<112::AID-CNCR16>3.0.CO;2-T
[23] G. Anker, P. E. Lonning, P. M. Ueland, H. Refsum and E. A. Lien, “Plasma Levels of the Atherogenic Amino Acid Homocysteine in Post-Menopausal Women with Breast Cancer Treated with Tamoxifen,” International Journal of Cancer, Vol. 60, No. 3, 1995, pp. 365-368. doi:10.1002/ijc.2910600316
[24] M. Cattaneo, L. Baglietto, M. L. Zighetti, D. Bettega, C. Robertson, A. Costa, P. M. Mannucci and A. Decensi, “Tamoxifen Reduces Plasma Homocysteine Levels in Healthy Women,” British Journal of Cancer, Vol. 77, 1998, pp. 2264-2266. doi:10.1038/bjc.1998.376
[25] G. Almadori, F. Bussu, J. Galli, G. Cadoni, B. Zappacosta, S. Persichilli, A. Minucci, B. Giardina and M. Maurizi, “Serum Levels of Folate, Homocysteine, and Vitamin B12 in Head and Neck Squamous Cell Carcinoma and in Laryngeal Leukoplakia,” Cancer, Vol. 103, No. 2, 2005, pp. 284-292. doi:10.1002/cncr.20772
[26] Y. C. Chou, M. S. Lee, M. H. Wu, H. L. Shih, T. Yang, C. P. Yu, J. C. Yu and C. A. Sun, “Plasma Homocysteine as a Metabolic Risk Factor for Breast Cancer: Findings from a Case-Control Study in Taiwan,” Breast Cancer Research and Treatment, Vol. 101, No. 2, 2007, pp. 199-205. doi:10.1007/s10549-006-9278-9
[27] F. L. Sciacca, E. Ciusani, A. Silvani, E. Corsini, S. Frigerio, S. Pogliani, E. Parati, D. Croci, A. Boiardi and A. Salmaggi, “Genetic and Plasma Markers of Venous Thromboembolism in Patients with High Grade Glioma,” Clinical Cancer Research, Vol. 10, No. 4, 2004, pp. 1312-1317. doi:10.1158/1078-0432.CCR-03-0198
[28] G. Bobe, G. Murphy, C. J. Rogers, K. W. Hance, P. S. Albert, A. O. Laiyemo, L. B. Sansbury, E. Lanza, A. Schatzkin and A. J. Cross, “Serum Adiponectin, Leptin, C-Peptide, Homocysteine, and Colorectal Adenoma Recurrence in the Polyp Prevention Trial,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 19, No. 6, 2010, pp. 1441-1452. doi:10.1158/1055-9965.EPI-09-1082
[29] G. Almadori, F. Bussu, J. Galli, G. Cadoni, B. Zappacosta, S. Persichilli, A. Minucci and B. Giardina, “Serum Folate and Homocysteine Levels in Head and Neck Squamous Cell Carcinoma,” Cancer, Vol. 94, No. 4, 2002, pp. 1006-1011. doi:10.1002/cncr.10343
[30] Y. Ozkan, S. Yardim-Akaydin, H. Firat, E. Caliskan-Can, S. Ardic and B. Simsek, “Usefulness of Homocysteine as a Cancer Marker: Total Thiol Compounds and Folate Levels in Untreated Lung Cancer Patients,” Anticancer Research, Vol. 27, No. 2, 2007, pp. 1185-1189.
[31] K. Schroecksnadel, B. Frick, C. Winkler, L. C. Fuith and D. Fuchs, “Relationship between Homocysteine and Neopterin Concentrations in Patients with Gynecological Cancer,” Cancer Letters, Vol. 240, No. 2, 2006, pp. 198-202. doi:10.1016/j.canlet.2005.09.009
[32] M. J. Ellis, Y. Tao, J. Luo, R. A’Hern, D. B. Evans, A. S. Bhatnagar, H. A. Chaudri Ross, A. von Kameke, W. R. Miller, I. Smith, W. Eiermann and M. Dowsett, “Outcome Prediction for Estrogen Receptor-Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics,” Journal of the National Cancer Institute, Vol. 100, No. 19, 2008, pp. 1380-1388. doi:10.1093/jnci/djn309
[33] J. H. Seo, Y. H. Kim and J. S. Kim, “Meta-Analysis of Pre-Operative Aromatase Inhibitor versus Tamoxifen in Postmenopausal Woman with Hormone Receptor-Breast Cancer,” Cancer Chemotherapy and Pharmacology, Vol. 63, No. 2, 2009, pp. 261-266. doi:10.1007/s00280-008-0735-5

  
comments powered by Disqus

Copyright © 2017 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.