PT - JOURNAL ARTICLE AU - Mingjun Bi AU - Zhao Zhang AU - Pengya Xue AU - Karen Hernandez AU - Hu Wang AU - Xiaoyong Fu AU - Carmine De Angelis AU - Zhen Gao AU - Jianhua Ruan AU - Victor X. Jin AU - Qianben Wang AU - Elisabetta Marangoni AU - Tim Hui-Ming Huang AU - Lizhen Chen AU - Christopher K. Glass AU - Wei Li AU - Rachel Schiff AU - Zhijie Liu TI - Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance AID - 10.1101/767871 DP - 2019 Jan 01 TA - bioRxiv PG - 767871 4099 - http://biorxiv.org/content/early/2019/09/16/767871.short 4100 - http://biorxiv.org/content/early/2019/09/16/767871.full AB - Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERĪ± and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.