Arsenic induces functional re-expression of estrogen receptor α by demethylation of DNA in estrogen receptor-negative human breast cancer.
Arsenic induces functional re-expression of estrogen receptor α by demethylation of DNA in estrogen receptor-negative human breast cancer.
复制标题
DOI：
10.1371/journal.pone.0035957
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Du J;Zhou N;Liu H;Jiang F;Wang Y;Hu C;Qi H;Zhong C;Wang X;Li Z
雌激素受体α（ERα）是预测乳腺癌对内分泌治疗反应的标志物。然而，大约30%的乳腺癌是激素非依赖性的，因为缺乏ERα表达.需要新的策略来重新表达ERα并使ER阴性乳腺癌细胞对选择性ER调节剂敏感。目前的报告显示，三氧化二砷诱导再活化的ERα，提供了一个目标的治疗与ER拮抗剂。三氧化二砷可诱导ER阴性乳腺癌细胞ERα mRNA和功能性ERα蛋白的表达。荧光素酶报告基因测定和3-（4，5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-磺基苯基）-2H-四唑（MTS）测定显示，在暴露于三氧化二砷后，以前无反应的ER阴性MDA-MB-231乳腺癌细胞变得对ER拮抗剂、4-羟基他莫昔芬和ICI 182，780有反应。此外，甲基化特异性PCR和亚硫酸氢盐测序PCR分析表明，三氧化二砷诱导ERα启动子部分去甲基化。甲基供体S-腺苷甲硫氨酸（SAM）可降低三氧化二砷诱导的ERα再表达和去甲基化程度。Western blot和ChIP分析显示，三氧化二砷可抑制DNMT 1和DNMT 3a的表达，同时沿着DNMT 1与ERα启动子的部分解离。因此，三氧化二砷表现出一种以前未明确的功能，即通过ERα启动子的去甲基化诱导ER阴性乳腺癌细胞中ERα的重新表达。这些发现可以提供重要的信息，针对乳腺癌的表观遗传变化的治疗药物的应用和三氧化二砷作为一种新的药物用于治疗ER阴性的人乳腺癌的潜在意义。
Estrogen receptor α (ERα) is a marker predictive for response of breast cancers to endocrine therapy. About 30% of breast cancers, however, are hormone- independent because of lack of ERα expression. New strategies are needed for re-expression of ERα and sensitization of ER-negative breast cancer cells to selective ER modulators. The present report shows that arsenic trioxide induces reactivated ERα, providing a target for therapy with ER antagonists. Exposure of ER-negative breast cancer cells to arsenic trioxide leads to re-expression of ERα mRNA and functional ERα protein in in vitro and in vivo. Luciferase reporter gene assays and 3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assays show that, upon exposure to arsenic trioxide, formerly unresponsive, ER-negative MDA-MB-231 breast cancer cells become responsive to ER antagonists, 4-hydroxytamoxifen and ICI 182,780. Furthermore, methylation- specific PCR and bisulfite-sequencing PCR assays show that arsenic trioxide induces partial demethylation of the ERα promoter. A methyl donor, S-adenosylmethionine (SAM), reduces the degree of arsenic trioxide-induced re-expression of ERα and demethylation. Moreover, Western blot and ChIP assays show that arsenic trioxide represses expression of DNMT1 and DNMT3a along with partial dissociation of DNMT1 from the ERα promoter. Thus, arsenic trioxide exhibits a previously undefined function which induces re-expression ERα in ER-negative breast cancer cells through demethylation of the ERα promoter. These findings could provide important information regarding the application of therapeutic agents targeting epigenetic changes in breast cancers and potential implication of arsenic trioxide as a new drug for the treatment of ER–negative human breast cancer.
登录
查看更多内容
影响因子：
10.3
作者：
ROODI, N;BAILEY, LR;PARL, FF
通讯作者：
PARL, FF
影响因子：
50.5
作者：
JOHNSTON, SRD;DOWSETT, M;SMITH, IE
通讯作者：
SMITH, IE
影响因子：
4
作者：
Chow, SKY;Chan, JYW;Fung, KP
通讯作者：
Fung, KP
影响因子：
3.3
作者：
CROOKS, PA;TRIBE, MJ;PINNEY, RJ
通讯作者：
PINNEY, RJ
影响因子：
3.8
作者：
Rae, James M.;Creighton, Chad J.;Johnson, Michael D.
通讯作者：
Johnson, Michael D.