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CpG Island Methylation Profile of Estrogen Receptor Alpha in Iranian Females with Triple Negative or Non-triple Negative Breast Cancer: New Marker of Poor Prognosis

  • Ramezani, Fatemeh (Department of Clinical Biochemistry and Nutrition, Faculty of Medicine, Urmia University of Medical Sciences) ;
  • Salami, Siamak (Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences) ;
  • Omrani, Mir Davood (Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences) ;
  • Maleki, Davood (Department of Hematology and Oncology, Faculty of Medicine, Urmia University of Medical Sciences)
  • Published : 2012.02.29

Abstract

One decade early onset of the breast cancer in Iranian females was reported but the basis of the observed difference has remained unclear and difference in gene silencing by epigenetic processes is suggested. Hence, this study was sought to map the methylation status of estrogen receptor (ER) gene CpG islands and its impact on clinicopathological factors of triple negative and non-triple negative ductal cell carcinoma of the breast in Iranian females. Surgically resected formalin-fixed paraffin-embedded breast tissues from sixty Iranian women with confirmed invasive ductal carcinoma were assessed by methylation-specific PCR using primer sets encompassing some of the 29 CpGs across the ER gene CpG island. The estrogen and progesterone receptors, Her-$2^+$ overexpression, and nuclear accumulation of P53 were examined using immunohistochemistry (IHC). Methylated ER3, ER4, and ER5 were found in 41.7, 11.3, and 43.3% of the samples, respectively. Significantly higher methylation of ER4 was found in the tumors with nuclear accumulation of P53, and significantly higher methylation of ER5 was found in patients with lymph node involvement and tumor with bigger size or higher grades. Furthermore, significantly higher rate of ER5 methylation was found in patients with Her-$2^+$ tumors and in postmenopausal patients with $ER^-$, $PgR^-$, or $ER^-/PgR^-$ tumors. However, no significant difference in ERs methylation status was found between triple negative and non-triple negative tumors in pre- and postmenopausal patients. Findings revealed that aberrant hypermethylation of the ER-alpha gene frequently occurs in Iranian women with invasive ductal cell carcinoma of the breast. However, methylation of different CpG islands produced a diverse impact on the prognosis of breast cancer, and ER5 was found to be the most frequently methylated region in the Iranian women, and could serve as a marker of poor prognosis.

Keywords

Estrogen receptor alpha;CpG islands methylation;triple negative phenotype;breast cancer

References

  1. Ascenzi P, Bocedi A, Marino M (2006). Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med, 27, 299-402. https://doi.org/10.1016/j.mam.2006.07.001
  2. Bae YK, Brown A, Garrett E, et al (2004). Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res, 10, 5998-6005. https://doi.org/10.1158/1078-0432.CCR-04-0667
  3. Buyru N, Altinisik J, Ozdemir F, et al (2009). Methylation profiles in breast cancer. Cancer Invest, 27, 307-12. https://doi.org/10.1080/07357900802350814
  4. Conte P, Guarneri V (2009). Triple-negative breast cancer: current management and future options. Eur J Cancer, 7, 14-8.
  5. Giacinti L, Claudio PP, Lopez M, et al (2006). Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist, 11, 1-8.
  6. Hanstein B, Djahansouzi S, Dall P, et al (2004). Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer. Eur J Endocrinol, 150, 243-55. https://doi.org/10.1530/eje.0.1500243
  7. Harirchi I, Ebrahimi M, Zamani N, et al (2000). Breast cancer in Iran: a review of 903 case records. Public Health, 114, 143-5.
  8. Harris L, Fritsche H, Mennel R, et al (2007). American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 25, 5287-312. https://doi.org/10.1200/JCO.2007.14.2364
  9. Herman JG, Graff JR, Myohanen S, et al (1996). Methylationspecific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA, 93, 9821-6. https://doi.org/10.1073/pnas.93.18.9821
  10. Kolahdoozan S, Sadjadi A, Radmard AR, et al (2010). Five common cancers in Iran. Arch Iranian Med, 13, 143-6.
  11. Kos M, Reid G, Denger S, et al (2001). Minireview: genomic organization of the human ERalpha gene promoter region. Molec Endocrinol, 15, 2057-63. https://doi.org/10.1210/me.15.12.2057
  12. Lapidus RG, Nass SJ, Butash KA, et al (1998). Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res, 58, 2515-9.
  13. Le Romancer M, Treilleux I, Bouchekioua-Bouzaghou K, et al. (2010). Methylation, a key step for nongenomic estrogen signaling in breast tumors. Steroids, 75, 560-4. https://doi.org/10.1016/j.steroids.2010.01.013
  14. Lee JS, Fackler MJ, Teo WW, et al (2008). Quantitative promoter hypermethylation profiles of ductal carcinoma in situ in North American and Korean women: Potential applications for diagnosis. Cancer Biol Ther, 7, 1398-406.
  15. Liu C, Zhang H, Shuang C, et al (2009). Alternations of ER, PR, HER-2/neu, and P53 protein expression in ductal breast carcinomas and clinical implications. Med Oncol, 27, 747-52
  16. Macaluso M, Cinti C, Russo G, et al.(2003). pRb2/p130-E2F4/5- HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1- SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer. Oncogene, 22, 3511-7. https://doi.org/10.1038/sj.onc.1206578
  17. Mehrotra J, Vali M, McVeigh M, et al (2004). Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin Cancer Res, 10, 3104-9. https://doi.org/10.1158/1078-0432.CCR-03-0118
  18. Mirza S, Sharma G, Prasad CP, et al (2007). Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci, 81, 280-7. https://doi.org/10.1016/j.lfs.2007.05.012
  19. Mohagheghi MA, Mosavi-Jarrahi A, Malekzadeh R, et al (2009). Cancer incidence in Tehran metropolis: the first report from the Tehran Population-based Cancer Registry, 1998-2001. Arch Iranian Med, 12, 15-23.
  20. Mousavi SM, Mohaghegghi MA, Mousavi-Jerrahi A, et al (2006). Burden of breast cancer in Iran: a study of the Tehran population based cancer registry. Asian Pac J Cancer Prev, 7, 571-4.
  21. Mousavi SM, Mohagheghi MA, Mousavi-Jerrahi A, et al (2008). Outcome of breast cancer in Iran: a study of Tehran Cancer Registry data. Asian Pac J Cancer Prev, 9, 275-8.
  22. Mousavi SM, Montazeri A, Mohagheghi MA, et al (2007). Breast cancer in Iran: an epidemiological review. Breast J, 13, 383-91. https://doi.org/10.1111/j.1524-4741.2007.00446.x
  23. Parl FF (2003). Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer. Pharmacogenomics J, ?, 251-3. https://doi.org/10.1038/sj.tpj.6500201
  24. Parrella P, Poeta ML, Gallo AP, et al (2004). Nonrandom distribution of aberrant promoter methylation of cancerrelated genes in sporadic breast tumors. Clin Cancer Res, 10, 5349-54. https://doi.org/10.1158/1078-0432.CCR-04-0555
  25. Pinzone JJ, Stevenson H, Strobl JS, et al (2004). Molecular and cellular determinants of estrogen receptor alpha expression. Mol Cell Biol, 24, 4605-12. https://doi.org/10.1128/MCB.24.11.4605-4612.2004
  26. Rasti M, Entezam M , Monabati A (2009). Hypermethylation of E-cadherin and estrogen receptor gene promoter and its association with clinicopathological features of breast cancer in Iranian patients. Iran J Medical Sci, 34, 186-92.
  27. Riggins RB, Schrecengost RS, Guerrero MS, et al (2007). Pathways to tamoxifen resistance. Cancer Letters, 256, 1-24. https://doi.org/10.1016/j.canlet.2007.03.016
  28. Sadjadi A, Nouraie M, Mohagheghi MA, et al (2005). Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev, 6, 359-63.
  29. Salami S, Karami-Tehrani F (2003). Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines. Clin Biochem, 36, 247-53. https://doi.org/10.1016/S0009-9120(03)00007-9
  30. Salami S, Ramezani F, Aghazadeh T, et al (2011). Impact of triple negative phenotype on prognosis and early onset of breast cancer in Iranian females. Asian Pac J Cancer Prev, 12, 719-24.
  31. Seal MD, Chia SK (2010). What is the difference between triple-negative and basal breast cancers? Cancer J, 16, 12-6. https://doi.org/10.1097/PPO.0b013e3181cf04be
  32. Szyf M, Pakneshan P, Rabbani SA (2004). DNA methylation and breast cancer. Biochem Pharmacol, 68, 1187-97. https://doi.org/10.1016/j.bcp.2004.04.030
  33. Vahdaninia M , Montazeri A (2004). Breast cancer in Iran: a survival analysis. Asian Pac J Cancer Prev, 5, 223-5.
  34. Viale G , Bottiglieri L (2009). Pathological definition of triple negative breast cancer. Eur J Cancer, 45, 5-10. https://doi.org/10.1016/S0959-8049(09)70011-5
  35. Wei M, Xu J, Dignam J, et al (2008). Estrogen receptor alpha, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers. Breast Cancer Res Treat, 111, 113-20. https://doi.org/10.1007/s10549-007-9766-6
  36. Yoshida T, Eguchi H, Nakachi K, et al (2000). Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. Carcinogenesis, 21, 2193-201. https://doi.org/10.1093/carcin/21.12.2193
  37. Zhao L, Wang L, Jin F, et al (2008). Silencing of estrogen receptor alpha (ERalpha) gene by promoter hypermethylation is a frequent event in Chinese women with sporadic breast cancer. Breast Cancer Res Treat, 117, 253-9.

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