Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis
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 α (ERα) 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 ERα 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 ERα 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 31, 2018
- Source ID
- 10.1158/0008-5472.can-17-1327
Entities
People
- Carmine De Angelis
- Cecilia J Proietti
- Huai-chin Chiang
- Kexin Xu
- Matias Amasino
- Mauro E. Cenciarini
- Mei Yang
- Myles A. Brown
- Patricia V Elizalde
- Rachel Schiff
- Ratna K Vadlamudi
- Rinath Jeselsohn
- Rong Li
- Tao Hong
- Tim H-M Huang
- Virginia G. Kaklamani
- Xiaoyong Fu
- Yanming Wu
- Yiji Liao
- Zhao Zhang
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Center for Strategic Scientific Initiatives, National Cancer Institute
- Central South University
- Dana–Farber Cancer Institute
- Harvard Medical School
- Instituto de Biología y Medicina Experimental
- Max and Minnie Tomerlin Voelcker Fund
- National Cancer Institute
- Susan G. Komen for the Cure
- The Breast Cancer Research Foundation
- United States Department of Defense
- University of Texas Health Science Center at San Antonio
- University of Texas System
- University of Texas at Austin
- V Foundation for Cancer Research