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

CENCIARINI MAURO E.; TAO HONG; ZHAO ZHANG; HUAI-CHIN CHIANG; AMASINO MATÍAS; RATNA K. VADLAMUDI; YIJI LIAO; CARMINE DE ANGELIS; RINATH JESELSOHN; RACHEL SCHIFF; RONG LI; ELIZALDE PATRICIA V.; KEXIN XU; YANMING WU; PROIETTI CECILIA J.; MEI YANG; VIRGINIA G. KAKLAMANI; TIM HUI-MING HUANG; XIAOYONG FU; MYLES BROWN

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2018 vol. 78 p. 671 - 684

0008-5472

Resistance to cancer treatment can be driven by epigenetic reprogrammingof specific transcriptomes in favor of the refractoryphenotypes. Here we discover that tamoxifen resistance in breastcancer is driven by a regulatory axis consisting of a master transcriptionfactor, its cofactor, and an epigenetic regulator. The oncogenichistone methyltransferase EZH2 conferred tamoxifen resistance bysilencing the expression of the estrogen receptor a (ERa) cofactorGREB1. In clinical specimens, induction of DNA methylation of aparticular CpG-enriched region at the GREB1 promoter negativelycorrelated with GREB1 levels and cell sensitivity to endocrine agents.GREB1 also ensured proper cellular reactions to different ligands byrecruiting distinct sets of ERa cofactors to cis-regulatory elements,which explains the contradictory biological effects of GREB1 onbreast cancer cell growth in response to estrogen or antiestrogen. Inrefractory cells, EZH2-dependent repression of GREB1 triggeredchromatin reallocation of ERa coregulators, converting the antiestrogeninto an agonist. In clinical specimens frompatients receivingadjuvant tamoxifen treatment, expression levels of EZH2 andGREB1 were correlated negatively, and taken together better predictedpatient responses to endocrine therapy. Overall, our worksuggests a new strategy to overcome endocrine resistance in metastaticbreast cancer by targeting a particular epigenetic program.Significance: This study suggests a new strategy to overcomeendocrine resistance in metastatic breast cancer bytargeting a particular epigenetic program defined within. CancerRes; 78(3); 671?84. 2017 AACR.