Absence of Metallothionein 3 Expression in Breast Cancer is a Rare, But Favorable Marker of Outcome that is Under Epigenetic Control.
Absence of Metallothionein 3 Expression in Breast Cancer is a Rare, But Favorable Marker of Outcome that is Under Epigenetic Control.
复制标题
乳腺癌中金属硫蛋白 3 表达的缺失是一种罕见但有利的结果标志，受表观遗传控制。
DOI：
10.1080/02772241003711274
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发表时间：
2010
影响因子：
1.8
通讯作者：
Sens,MaryAnn
中科院分区：
文献类型：
--
作者：
Somji,Seema;Garrett,ScottH;Zhou,XuDong;Zheng,Yun;Sens,DonaldA;Sens,MaryAnn
镉（Cd 2+）是一种已知的致癌物，它模拟雌激素在子宫和乳腺中的作用，表明它可能参与乳腺癌的发生和进展。该实验室通过对一小组存档的人类诊断标本的分析表明，经典Cd 2+结合蛋白金属硫蛋白（MT-3）的第三种亚型在正常乳腺组织中不表达，但在某些乳腺癌中表达，并且该表达往往与不良疾病结局相关。本研究的目的是验证MT-3在大量人类诊断标本中的过度表达与疾病预后不良相关，并确定正常乳腺上皮细胞中MT-3基因调控的机制。结果显示，MT-3在所有乳腺癌中表达的比例约为90%，而在正常乳腺上皮中不表达。在某些癌症中缺乏MT-3染色与有利的患者结局相关。原位乳腺癌MT-3阳性率高，提示MT-3可能是乳腺癌的早期生物标志物。该研究还表明，MCF-10A细胞系，一种永生化的，非致瘤性的人乳腺上皮细胞模型，没有显示MT-3的基础表达，也没有被Cd 2+诱导。用去甲基化剂5-氮-2 ′-脱氧胞苷或组蛋白去乙酰化酶抑制剂MS-275处理MCF-10A细胞，可恢复MT-3 mRNA的表达。还显示MT-3金属调节元件在用这些抑制剂处理后是蛋白因子的潜在活性结合剂，表明MT-3表达可能受到表观遗传调节。
Cadmium (Cd2+), a known carcinogen, mimics the effects of estrogen in the uterus and mammary gland suggesting its possible involvement in the development and progression of breast cancer. This lab showed through analysis of a small set of archival human diagnostic specimens that the third isoform of the classic Cd2+binding protein metallothionein (MT-3) is not expressed in normal breast tissue, but is expressed in some breast cancers and that expression tends to correlate with a poor disease outcome. The goals of this study were to verify that overexpression of MT-3 in a large set of archival human diagnostic specimens tends to correlate with poor disease outcome and define the mechanism of MT-3 gene regulation in the normal breast epithelial cell. The results showed that MT-3 was expressed in approximately 90% of all breast cancers and was absent in normal breast epithelium. The lack of MT-3 staining in some cancers correlated with a favorable patient outcome. High frequency of MT-3 staining was also found forin situbreast cancer suggesting that MT-3 might be an early biomarker for breast cancer. The study also demonstrated that the MCF-10A cell line, an immortalized, non-tumorigenic model of human breast epithelial cells, displayed no basal expression of MT-3, nor was it induced by Cd2+. Treatment of the MCF-10A cells with the demethylation agent, 5-aza-2′-deoxycytidine, or the histone deacetylase inhibitor, MS-275, restored MT-3 mRNA expression. It was also shown that the MT-3 metal regulatory elements are potentially active binders of protein factors following treatment with these inhibitors suggesting that MT-3 expression may be subject to epigenetic regulation.