@article{890d48f16d23491b84e8722ae0727f37,
title = "Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance",
abstract = "Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.",
author = "Mingjun Bi and Zhao Zhang and Jiang, {Yi Zhou} and Pengya Xue and Hu Wang and Zhao Lai and Xiaoyong Fu and {De Angelis}, Carmine and Yue Gong and Zhen Gao and Jianhua Ruan and Jin, {Victor X.} and Elisabetta Marangoni and Elodie Montaudon and Glass, {Christopher K.} and Wei Li and Huang, {Tim Hui Ming} and Shao, {Zhi Ming} and Rachel Schiff and Lizhen Chen and Zhijie Liu",
note = "Funding Information: Z. Liu is a CPRIT Scholar in Cancer Research. This work was supported by grants to Z. Liu via a CPRIT award (RR160017), V Foundation{\textquoteright}s V Scholar Award (V2016-017) and V Scholar Plus Award (DVP2019-018), Max and Minnie Tomerlin Voelcker Fund Young Investigator Award, a Susan G. Komen CCR award (CCR17483391), a National Cancer Institute grant (U54 CA217297/PRJ001) and a UT Rising STARs Award. Research reported in this publication was also supported by the NIGMS of the NIH under Award Number R01GM137009 to Z. Liu. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. All deep sequencing data were generated in the Genome Sequencing Facility at Greehey Children{\textquoteright}s Cancer Research Institute in the UT Health San Antonio, which is supported by NIH-NCI P30 CA054174 (NIH Cancer Center at UT Health San Antonio), an NIH Shared Instrument grant 1S10OD021805-01 (S10 grant) and a CPRIT Core Facility Award (RP160732). BASiC, where pyrosequencing assay experiments were carried out, was supported by the CPRIT award (RP150600) and funding from the Office of the Vice President of Research, UTHSCSA. R.S. and X.F. were supported by NIH SPORE grants (P50 CA058183 and CA186784 to R.S.), Cancer Center grants (P30 CA125123 to R.S. and X.F.), the Breast Cancer Research Foundation (BCRF-17-143, 18-145 and 19-145 to R.S.), CPRIT grant no. RP190398 (R.S. and X.F.) and a DOD grant (W81XWH-14-1-0326 to X.F.).",
year = "2020",
month = jun,
day = "1",
doi = "10.1038/s41556-020-0514-z",
language = "English (US)",
volume = "22",
pages = "701--715",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "6",
}