Open AccessEnhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance
Author(s) -
Mingjun Bi,
Zhao Zhang,
YiZhou Jiang,
Pengya Xue,
Hu Wang,
Zhao Lai,
Xiaoyong Fu,
Carmine De Angelis,
Yue Gong,
Gao Z,
Jianhua Ruan,
Victor X. Jin,
Elisabetta Marangoni,
Élodie Montaudon,
Christopher K. Glass,
Wei Li,
Tim Hui-Ming Huang,
ZhiMing Shao,
Rachel Schiff,
Lizhen Chen,
Zhijie Liu
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-0514-z
Subject(s) - reprogramming , enhancer , biology , gata3 , ap 1 transcription factor , transcription factor , cancer research , downregulation and upregulation , phenotype , microbiology and biotechnology , breast cancer , cancer , genetics , gene
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.