INVESTIGADORES
PROIETTI ANASTASI Cecilia Jazmin
artículos
Título:
Transcriptional Axis of EZH2-ER alpha;-GREB1 Regulates Tamoxifen Resistance in Breast Cancer
Autor/es:
YANMING WU; ZHAO ZHANG; MAURO EZEQUIEL CENCIARINI; CECILIA J PROIETTI; MATIAS AMASINO; TAO HONG; MEI YANG; YIJI LIAO; HUAI-CHIN CHIANG; VIRGINIA KAKLAMANI; RINATH JESELSOHN; RATNA K. VADLAMUDI; TIM HUI-MING HUANG; RONG LI; CARMINE DE ANGELIS; XIAOYONG FU; PATRICIA V ELIZALDE; RACHEL SCHIFF; MYLES BROWN; KEXIN XU
Revista:
CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Lugar: Philadelphia; Año: 2018
ISSN:
0008-5472
Resumen:
Loss of responsiveness to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discovered a critical transcriptional axis consisting of a master transcription factor, its cofactor and an epigenetic regulator in driving tamoxifen resistant breast cancer. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, confers tamoxifen resistance by inducing an estrogen receptor α (ERα)-regulated transcriptional program that dictates drug response. EZH2 silences the expression of ERα cofactor GREB1 by inducing DNA methylation of a particular CpG-enriched region at GREB1 promoter, which is negatively correlated with GREB1 levels in clinical scenario and highly associated with cell sensitivity to endocrine agents. We also revealed a novel function of GREB1 in ensuring proper cellular reactions to different ligands by recruiting essentially 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 anti-estrogen. EZH2-dependent repression of GREB1 in refractory cells results in chromatin reallocation of ERα coregulators, converting the anti-estrogen into an agonist. Levels of EZH2 and GREB1 are negatively correlated in clinical samples receiving adjuvant tamoxifen treatment, and together better predict patients? responses to endocrine therapy. In summary, our work provides a novel therapeutic strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program for the concerted blockade of therapy resistance-driving axis.