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
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
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DOI：
10.7314/apjcp.2012.13.2.451
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Maleki, Davood
中科院分区：
文献类型：
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作者：
Ramezani, Fatemeh;Salami, Siamak;Maleki, Davood
据报道，伊朗女性乳腺癌发病早了十年，但观察到的差异的基础仍不清楚，并建议通过表观遗传过程进行基因沉默。因此，本研究旨在绘制雌激素受体（ER）基因CpG岛的甲基化状态及其对伊朗女性乳腺三阴性和非三阴性导管细胞癌临床病理因素的影响。手术切除的福尔马林固定石蜡包埋的乳腺组织，从60名伊朗妇女确诊为浸润性导管癌进行了评估，甲基化特异性PCR引物组包括一些29个CpG在ER基因CpG岛。采用免疫组化（IHC）法检测雌、孕激素受体、Her-2（+）过表达和P53核内聚集。甲基化ER 3、ER 4和ER 5分别见于41.7%、11.3%和43.3%的样本中。ER 4甲基化水平在P53核内聚集的肿瘤中显著增高，ER 5甲基化水平在淋巴结转移、肿瘤体积较大或级别较高的患者中显著增高。此外，在Her-2（+）肿瘤患者和ER-、PgR-或ER-/PgR-肿瘤绝经后患者中发现ER 5甲基化率显著较高。然而，在绝经前和绝经后患者中，三阴性和非三阴性肿瘤之间ER甲基化状态没有显著差异。研究结果显示，ER-α基因的异常高甲基化经常发生在伊朗妇女的乳腺浸润性导管细胞癌。然而，不同CpG岛的甲基化对乳腺癌的预后产生不同的影响，并且发现ER 5是伊朗妇女中最常见的甲基化区域，并且可以作为预后不良的标志。
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.