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

被引：84

作者：

Wu, Yanming ^{[1
]}

Zhang, Zhao ^{[1
]}

Cenciarini, Mauro E. ^{[2
]}

Proietti, Cecilia J. ^{[2
]}

Amasino, Matias ^{[2
]}

Hong, Tao ^{[1
,3
]}

Yang, Mei ^{[1
]}

Liao, Yiji ^{[1
]}

Chiang, Huai-Chin ^{[1
,4
]}

Kaklamani, Virginia G. ^{[5
]}

Jeselsohn, Rinath ^{[6
,7
,8
]}

Vadlamudi, Ratna K. ^{[9
]}

Huang, Tim Hui-Ming ^{[1
,4
]}

Li, Rong ^{[1
,4
]}

De Angelis, Carmine ^{[10
]}

Fu, Xiaoyong ^{[10
]}

Elizalde, Patricia V. ^{[2
]}

Schiff, Rachel ^{[10
,11
]}

Brown, Myles ^{[6
,7
,8
]}

Xu, Kexin ^{[1
,4
]}

机构：

[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA

[2] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Lab Mol Mech Carcinogenesis, Buenos Aires, DF, Argentina

[3] Cent S Univ, Xiangya Sch Med, Changsha, Hunan, Peoples R China

[4] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA

[5] Univ Texas San Antonio, Canc Therapy & Res Ctr, Sch Med, Div Hematol Oncol,Breast Canc Program, San Antonio, TX USA

[6] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA

[7] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA

[8] Harvard Med Sch, Dept Med, Boston, MA USA

[9] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA

[10] Baylor Coll Med, Dan L Duncan Canc Ctr, Lester & Sue Smith Breast Ctr, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[11] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

来源：

CANCER RESEARCH | 2018年 / 78卷 / 03期

关键词：

DNA METHYLATION; METHYLTRANSFERASE EZH2; PROSTATE-CANCER; THERAPY; GREB1; INHIBITION; EXPRESSION; LYMPHOMA; TUMORS; CELLS;

D O I：

10.1158/0008-5472.CAN-17-1327

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 alpha (ER alpha) 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 ER alpha 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. (C) 2017 AACR.

引用

页码：671 / 684

页数：14

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