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http://dx.doi.org/10.7314/APJCP.2012.13.2.451

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)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.2, 2012 , pp. 451-457 More about this Journal
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;
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1 Bae YK, Brown A, Garrett E, et al (2004). Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res, 10, 5998-6005.   DOI   ScienceOn
2 Buyru N, Altinisik J, Ozdemir F, et al (2009). Methylation profiles in breast cancer. Cancer Invest, 27, 307-12.   DOI   ScienceOn
3 Conte P, Guarneri V (2009). Triple-negative breast cancer: current management and future options. Eur J Cancer, 7, 14-8.
4 Giacinti L, Claudio PP, Lopez M, et al (2006). Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist, 11, 1-8.
5 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.   DOI   ScienceOn
6 Harirchi I, Ebrahimi M, Zamani N, et al (2000). Breast cancer in Iran: a review of 903 case records. Public Health, 114, 143-5.
7 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.   DOI   ScienceOn
8 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.   DOI   ScienceOn
9 Kolahdoozan S, Sadjadi A, Radmard AR, et al (2010). Five common cancers in Iran. Arch Iranian Med, 13, 143-6.
10 Kos M, Reid G, Denger S, et al (2001). Minireview: genomic organization of the human ERalpha gene promoter region. Molec Endocrinol, 15, 2057-63.   DOI
11 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.
12 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.   DOI
13 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.
14 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
15 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.   DOI
16 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.   DOI   ScienceOn
17 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.   DOI
18 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.
19 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.
20 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.
21 Mousavi SM, Montazeri A, Mohagheghi MA, et al (2007). Breast cancer in Iran: an epidemiological review. Breast J, 13, 383-91.   DOI
22 Parl FF (2003). Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer. Pharmacogenomics J, ?, 251-3.   DOI
23 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.   DOI
24 Pinzone JJ, Stevenson H, Strobl JS, et al (2004). Molecular and cellular determinants of estrogen receptor alpha expression. Mol Cell Biol, 24, 4605-12.   DOI
25 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.
26 Riggins RB, Schrecengost RS, Guerrero MS, et al (2007). Pathways to tamoxifen resistance. Cancer Letters, 256, 1-24.   DOI
27 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.
28 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.   DOI
29 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.
30 Seal MD, Chia SK (2010). What is the difference between triple-negative and basal breast cancers? Cancer J, 16, 12-6.   DOI
31 Szyf M, Pakneshan P, Rabbani SA (2004). DNA methylation and breast cancer. Biochem Pharmacol, 68, 1187-97.   DOI   ScienceOn
32 Vahdaninia M , Montazeri A (2004). Breast cancer in Iran: a survival analysis. Asian Pac J Cancer Prev, 5, 223-5.
33 Viale G , Bottiglieri L (2009). Pathological definition of triple negative breast cancer. Eur J Cancer, 45, 5-10.   DOI
34 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.   DOI
35 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.   DOI
36 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.
37 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.   DOI