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

Significance Tamoxifen is beneficial in treating estrogen receptor–positive breast cancer, but resistance to this treatment eventually ensues. A method to identify mechanisms of tamoxifen resistance identified the histone deacetylase ZIP, leading to the finding that increased expression of the tyrosine kinase JAK2 is one important factor. As a result of this discovery, it may be possible to use an inhibitor of JAK2 to block the aberrant activation of STAT3 caused by ZIP deficiency to help overcome or prevent tamoxifen resistance.
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.