Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis

Yanming Wu, Zhao Zhang, Mauro E. Cenciarini, Cecilia J. Proietti, Matias Amasino, Tao Hong, Mei Yang, Yiji Liao, Huai Chin Chiang, Virginia G. Kaklamani, Rinath Jeselsohn, Ratna K. Vadlamudi, Tim Hui Ming Huang, Rong Li, Carmine De Angelis, Xiaoyong Fu, Patricia V. Elizalde, Rachel Schiff, Myles Brown, Kexin Xu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within.

Original languageEnglish (US)
Pages (from-to)671-684
Number of pages14
JournalCancer Research
Volume78
Issue number3
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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