Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer

文献类型： 外文期刊

第一作者： Zhu, Ning

作者： Zhu, Ning;Yang, Jinbo;Zhu, Ning;Du, Yuping;Miao, Ruidong;Nan, Jing;Sun, Jingjie;Zhao, Rui;Shi, Lei;Li, Xin;Lin, Yuxi;Wei, Wei;Yang, Jinbo;Zhu, Ning;Zhu, Ning;Zhang, Jing;Qin, Xiaodong;Nan, Jing;Chen, Xing;Stark, George R.;Wang, Yuxin;Zhang, Xinxin;Yang, Jinbo;Mao, Aihong;Mao, Aihong;Zhang, Zhao

作者机构：

关键词： tamoxifen resistance; JAK/STAT; ZIP; VBIM

期刊名称：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA （ 影响因子：11.205； 五年影响因子：12.291 ）

ISSN： 0027-8424

年卷期： 2020 年 117 卷 26 期

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收录情况： SCI

摘要： Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2. By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.

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