TY - JOUR
T1 - Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
AU - Wu, Yanming
AU - Zhang, Zhao
AU - Cenciarini, Mauro E.
AU - Proietti, Cecilia J.
AU - Amasino, Matias
AU - Hong, Tao
AU - Yang, Mei
AU - Liao, Yiji
AU - Chiang, Huai Chin
AU - Kaklamani, Virginia G.
AU - Jeselsohn, Rinath
AU - Vadlamudi, Ratna K.
AU - Huang, Tim Hui Ming
AU - Li, Rong
AU - De Angelis, Carmine
AU - Fu, Xiaoyong
AU - Elizalde, Patricia V.
AU - Schiff, Rachel
AU - Brown, Myles
AU - Xu, Kexin
N1 - Funding Information:
The authors sincerely thank Dr. Ya-Ting Hsu in Tim Hui-Ming Huang's group for technical support. We extremely appreciate Dr. Alfredo Molinolo and Dr. Roxana Schillaci for their valuable assistance in IHC procedure. We are also very grateful to Mrs. Sandi Stanford and Dr. Andrew Brenner for their insightful advices and discussion on this study. This work was supported by grants from CPRIT award (RR140072 to K. Xu), V Foundation Translational award (T2017-010 to K. Xu) and Voelcker Fund Young Investigator award (to K. Xu). BASiC, where the pyrosequencing was carried out, was supported by the CPRIT award (RP150600) and funding from the Office of Vice President of Research, UTHSCSA. The study was also partly supported by the National Cancer Institute-Argentina (2016, to C.J. Proietti), Grant Fondation Nelia et Amadeo Barletta, and PID 2012-066 from the National Agency of Scientific Promotion of Argentina (ANPCyT, to P.V. Elizalde), the Breast Cancer Research Foundation (to R. Schiff), Susan G. Komen for the Cure Foundation Promise Grants (PG12221410 to R. Schiff), Department of Defense Breakthrough Award (W81XWH-14-1-0326 to X. Fu), and National Cancer Institute grant (5P01CA080111-19 to M. Brown).
Funding Information:
R. Schiff reports receiving a commercial research grant from AstraZeneca. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-1327
DO - 10.1158/0008-5472.CAN-17-1327
M3 - Article
C2 - 29212856
AN - SCOPUS:85041470633
SN - 0008-5472
VL - 78
SP - 671
EP - 684
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -