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

Proceedings of the National Academy of Sciences of the United States of America
Ning ZhuJinbo Yang

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 ER-positive breast cancer.

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Methods Mentioned

BETA
acetylation
PCR
Immunoprecipitation
ChIP
ChIP-seq
Assay
transfection
electrophoresis
immunoprecipitation assay
histone

Software Mentioned

Hiseq
Blast

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