%0 Journal Article
%T Arsenic Induces Functional Re-Expression of Estrogen Receptor ¦Á by Demethylation of DNA in Estrogen Receptor-Negative Human Breast Cancer
%A Juan Du
%A Nannan Zhou
%A Hongxia Liu
%A Fei Jiang
%A Yubang Wang
%A Chunyan Hu
%A Hong Qi
%A Caiyun Zhong
%A Xinru Wang
%A Zhong Li
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0035957
%X Estrogen receptor ¦Á (ER¦Á) 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 ER¦Á expression. New strategies are needed for re-expression of ER¦Á and sensitization of ER-negative breast cancer cells to selective ER modulators. The present report shows that arsenic trioxide induces reactivated ER¦Á, providing a target for therapy with ER antagonists. Exposure of ER-negative breast cancer cells to arsenic trioxide leads to re-expression of ER¦Á mRNA and functional ER¦Á 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 ER¦Á promoter. A methyl donor, S-adenosylmethionine (SAM), reduces the degree of arsenic trioxide-induced re-expression of ER¦Á 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 ER¦Á promoter. Thus, arsenic trioxide exhibits a previously undefined function which induces re-expression ER¦Á in ER-negative breast cancer cells through demethylation of the ER¦Á 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¨Cnegative human breast cancer.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0035957