Volume 11, Issue 1 (Vol.11 No.1 Apr 2022)                   rbmb.net 2022, 11(1): 20-29 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Ahmed Aglan S, Mohamad Zaki A, Sobhy El Sedfy A, Gaber El-Sheredy H, Hussein Elgaddar O. O6-Methylguanine-DNA Methyltransferase and ATP-Binding Cassette Membrane Transporter G2 Promotor Methylation: Can Predict the Response to Chemotherapy in Advanced Breast Cancer?. rbmb.net 2022; 11 (1) :20-29
URL: http://rbmb.net/article-1-788-en.html
Department of Cancer Management and Research, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Abstract:   (2467 Views)
Background: ATP-binding cassette membrane transporter G2 (ABCG2) gene is one of transporter family and well characterized for their association with chemoresistance. Promoter methylation is a mechanism for regulation of gene expression. O6-Methyl guanine DNA methyl transferase (MGMT) gene plays a fundamental role in DNA repair. MGMT has the ability to remove alkyl adducts from DNA at the O6 position of guanine. Alkylating agents exert their function through adding these alkyls adducts to DNA leading to cell death unless it is repaired by MGMT. MGMT promoter was found to be methylated in several malignancies. The aim of the present work is to study the relation of MGMT and ABCG2 promoter methylation status in advanced breast cancer patients to response to cyclophosphamide–doxorubicin (AC) based therapeutic regime.

Methods: This retrospective study included Forty-two female patients with advanced breast cancer assessed before receiving chemotherapy and after the completion of regimens. They were grouped into responders and non-responders according to RECIST criteria. Methylation analysis of MGMT and
ABCG2 genes were performed on breast cancer tissues.

Results: MGMT promoter was methylated in 40.5% of the cases. ABCG2 promoter was methylated in 14.3% of cases. There was no statistically significant association between MGMT and ABCG2 promoter methylation status and clinicopathological parameters. There was statistically significant association between methylation status of both promoters and response to AC when followed by Taxane.

Conclusions: Methylation of MGMT and ABCG2 promoters combined could be a potential predictive factor for response to cyclophosphamide-doxorubicin based therapeutic regime.
Full-Text [PDF 274 kb]   (964 Downloads)    
Type of Article: Original Article | Subject: Molecular Biology
Received: 2021/09/18 | Accepted: 2021/11/2 | Published: 2022/05/26

1. Vidal M, Paré L, Prat A. Molecular Classification of Breast Cancer. In: Management of Breast Diseases. Jatoi I, Rody A (eds). 2nd ed. Springer International Publishing, Switzerland. 2016, 203-20. [DOI:10.1007/978-3-319-46356-8_12]
2. Di Leo A, Curigliano G, Diéras V, Malorni L, Sotiriou C, Swanton C, et al. New approaches for improving outcomes in breast cancer in Europe. Breast 2015;24(4):321-30. [DOI:10.1016/j.breast.2015.03.001] [PMID]
3. Klutstein M, Moss J, Kaplan T, Cedar H. Contribution of epigenetic mechanisms to variation in cancer risk among tissues. PNAS. 2017;114(9):2230-4. [DOI:10.1073/pnas.1616556114] [PMID] [PMCID]
4. Nourolahzadeh Z, Houshmand M, Mohammad FM, Ghorbian S. Correlation between Lsp1 (Rs3817198) and Casc (Rs4784227) Polymorphisms and the Susceptibility to Breast Cancer. Rep Biochem Mol Biol. 2020;9(3):291-296. [DOI:10.29252/rbmb.9.3.291] [PMID] [PMCID]
5. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. [DOI:10.1056/NEJMoa043331] [PMID]
6. Wang H, Yan W, Zhang S, Gu Y, Wang Y, Wei Y, et al. Survival differences of CIMP subtypes integrated with CNA information in human breast cancer. Oncotarget. 2017;8(30):48807-48819. [DOI:10.18632/oncotarget.16178] [PMID] [PMCID]
7. Fang F, Turcan S, Rimner A, Kaufman A, Giri D, Morris LG, et al. Breast cancer methylomes establish an epigenomic foundation for metastasis. Sci Transl Med. 2011;3(75):75ra25. [DOI:10.1126/scitranslmed.3001875] [PMID] [PMCID]
8. Roessler J, Ammerpohl O, Gutwein J, Steinemann D, Schlegelberger B, Weyer V, et al. The CpG island methylator phenotype in breast cancer is associated with the lobular subtype. Epigenomics. 2015;7(2):187-99. [DOI:10.2217/epi.14.74] [PMID]
9. Friedman HS, Pegg AE, Johnson SP, Loktionova NA, Dolan ME, Modrich P, et al. Modulation of cyclophosphamide activity by O 6-alkylguanine-DNA alkyltransferase. Cancer Chemother Pharmacol. 1999;43(1):80-5. [DOI:10.1007/s002800050866] [PMID]
10. Doyle L, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene. 2003;22(47):7340-58. [DOI:10.1038/sj.onc.1206938] [PMID]
11. Mo W, Zhang JT. Human ABCG2: structure, function, and its role in multidrug resistance. Int J Biochem Mol Biol. 2012;3(1):1-27.
12. Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012;83(8):1084-1103. [DOI:10.1016/j.bcp.2012.01.002] [PMID] [PMCID]
13. Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF. Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol. 2016;43(8):723-37. [DOI:10.1111/1440-1681.12581] [PMID]
14. Moon HH, Kim SH, Ku JL. Correlation between the promoter methylation status of ATP-binding cassette sub-family G member 2 and drug sensitivity in colorectal cancer cell lines. Oncol Rep. 2016;35(1):298-306. [DOI:10.3892/or.2015.4342] [PMID]
15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. [DOI:10.1016/j.ejca.2008.10.026] [PMID]
16. Rakha E, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207. [DOI:10.1186/bcr2607] [PMID] [PMCID]
17. Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013;31(31):3997-4013. [DOI:10.1200/JCO.2013.50.9984] [PMID]
18. Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. J Oncol Pract. 2010;6(4):195-197. [DOI:10.1200/JOP.777003] [PMID] [PMCID]
19. Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-Major Changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(4):290-303. [DOI:10.3322/caac.21393] [PMID]
20. Liu T, Xu F, Du X, Lai D, Liu T, Zhao Y, et al. Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1. Mol Cell Biochem. 2010;340(1-2):265-73. [DOI:10.1007/s11010-010-0426-5] [PMID]
21. Uno M, Oba-Shinjo SM, Camargo AA, Moura RP, Aguiar PH, Cabrera HN, et al. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma. Clinics (Sao Paulo) 2011;66(10):1747-1755. [DOI:10.1590/S1807-59322011001000013] [PMID] [PMCID]
22. Field A. Discovery Statistics Using IBM SPSS Statistics. 4th Ed. SAGE Publications Ltd, London. 2013.
23. Soosanabadi M, Mirfakhraie R, Atanesyan L, Biglarian A, Moghadam FA, Rahimi M, et al. Application of Multiplex Ligation-Dependent Probe Amplification in Determining the Copy Number Alterations of HER Gene Family Membersin Invasive Ductal Breast Carcinoma. Rep Biochem Mol Biol. 2019;8(2):91-101.
24. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003; 21(6):968-75. [DOI:10.1200/JCO.2003.04.040] [PMID]
25. Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001; 19(6):1707-15. [DOI:10.1200/JCO.2001.19.6.1707] [PMID]
26. Biganzoli L. Prognostic and predictive factors. Cancer Treat Res. 2009;151:13-30. [DOI:10.1007/978-0-387-75115-3_2] [PMID]
27. Huober J, von Minckwitz G, Denkert C, Tesch H, Weiss E, Zahm DM, et al. Effect of neoadjuvant anthracycline-Taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat. 2010;124(1):133-40. [DOI:10.1007/s10549-010-1103-9] [PMID]
28. Liedtke C, Rody A, Gluz O, Baumann K, Beyer D, Kohls EB, et al. The prognostic impact of age in different molecular subtypes of breast cancer. Breast Cancer Res Treat. 2015;152(3):667-73. [DOI:10.1007/s10549-015-3491-3] [PMID]
29. Goorts B, van Nijnatten TJ, de Munck L, Moossdorff M, Heuts EM, de Boer M, et al. Clinical tumor stage is the most important predictor of pathological complete response rate after neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2017;163(1):83-91. [DOI:10.1007/s10549-017-4155-2] [PMID] [PMCID]
30. Saadatmand S, Bretveld R, Siesling S, Tilanus-Linthorst MM. Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients. BMJ. 2015;351:h4901. [DOI:10.1136/bmj.h4901] [PMID] [PMCID]
31. Darwish AD, Helal AM, Aly El-Din NH, Solaiman LL, Amin A. Breast cancer in women aging 35 years old and younger: The Egyptian National Cancer Institute (NCI) experience. Breast. 2017;31:1-8. [DOI:10.1016/j.breast.2016.09.018] [PMID]
32. Sharma G, Mirza S, Parshad R, Srivastava A, Gupta SD, Pandya P, et al. Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci. 2010;87(3-4):83-91. [DOI:10.1016/j.lfs.2010.05.001] [PMID]
33. Asiaf A, Ahmad ST, Malik AA, Aziz SA, Rasool Z, Masood A, et al. Protein expression and methylation of MGMT, a DNA repair gene and their correlation with clinicopathological parameters in invasive ductal carcinoma of the breast. Tumour Biol. 2015;36(8):6485-96. [DOI:10.1007/s13277-015-3339-9] [PMID]
34. An N, Shi Y, Ye P, Pan Z, Long X. Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis. Cell Physiol Biochem. 2017;42(6):2430-2440. [DOI:10.1159/000480196] [PMID]
35. Chen R, Zheng Y, Zhuo L, Wang S. Association between MGMT Promoter Methylation and Risk of Breast and Gynecologic Cancers: A Systematic Review and Meta-Analysis. Sci Rep 2017;7(1):12783. [DOI:10.1038/s41598-017-13208-3] [PMID] [PMCID]
36. Fumagalli C, Pruneri G, Possanzini P, Manzotti M, Barile M, Feroce I, et al. Methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene in triple-negative breast cancer patients. Breast Cancer Res Treat. 2012;134(1):131-7. [DOI:10.1007/s10549-011-1945-9] [PMID]
37. Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way. J Breast Health. 2015;11(2):59-66. [DOI:10.5152/tjbh.2015.1669] [PMID] [PMCID]
38. Fumagalli C, Pasqua SD, Bagnardi V, Cardillo A, Sporchia A, Colleoni M, et al. Prevalence and Clinicopathologic Correlates of O6-Methylguanine-DNA Methyltransferase Methylation Status in Patients with Triple-Negative Breast Cancer Treated Preoperatively by Alkylating Drugs. Clin Breast Cancer. 2014;14(4):285-90. [DOI:10.1016/j.clbc.2014.02.010] [PMID]

Add your comments about this article : Your username or Email:

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2015 All Rights Reserved | Reports of Biochemistry and Molecular Biology

Designed & Developed by : Yektaweb