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Cancer Res. 2018 Feb 1;78(3):671-684. doi: 10.1158/0008-5472.CAN-17-1327. Epub 2017 Dec 6.

Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ERα-GREB1 Transcriptional Axis.

Author information

1
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
2
Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
3
Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China.
4
Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.
5
Division of Hematology/Oncology, Breast Cancer Program, Cancer Therapy & Research Center, School of Medicine, University of Texas, San Antonio, Texas.
6
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
7
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
8
Department of Obstetrics and Gynecology, Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.
9
Department of Molecular and Cellular Biology, Lester & Sue Smith Breast Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston.
10
Department of Medicine, Baylor College of Medicine, Houston.
11
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas. XuK3@uthscsa.edu.
#
Contributed equally

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.Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671-84. ©2017 AACR.

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