Nature Cell Biology: Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance

Mingjun Bi 1Zhao Zhang 1Yi-Zhou Jiang 2Pengya Xue 1Hu Wang 1Zhao Lai 1Xiaoyong Fu 3Carmine De Angelis 3Yue Gong 2Zhen Gao 4Jianhua Ruan 1 4Victor X Jin 1Elisabetta Marangoni 5Elodie Montaudon 5Christopher K Glass 6Wei Li 7Tim Hui-Ming Huang 1Zhi-Ming Shao 2Rachel Schiff 3Lizhen Chen 8 9Zhijie Liu 10

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 tumors 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 cultures 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 tumor phenotypic plasticity and therapy resistance.

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