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

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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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 ERpositive breast cancer.

Original languageEnglish (US)
Pages (from-to)15047-15054
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number26
DOIs
StatePublished - Jun 30 2020
Externally publishedYes

Keywords

  • JAK/STAT
  • VBIM
  • ZIP
  • tamoxifen resistance

ASJC Scopus subject areas

  • General

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