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

Mingjun Bi, Zhao Zhang, Yi Zhou Jiang, Pengya Xue, Hu Wang, Zhao Lai, Xiaoyong Fu, Carmine De Angelis, Yue Gong, Zhen Gao, Jianhua Ruan, Victor X. Jin, Elisabetta Marangoni, Elodie Montaudon, Christopher K. Glass, Wei Li, Tim Hui Ming Huang, Zhi Ming Shao, Rachel Schiff, Lizhen ChenZhijie Liu

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)701-715
Number of pages15
JournalNature Cell Biology
Volume22
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Cell Biology

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    Bi, M., Zhang, Z., Jiang, Y. Z., Xue, P., Wang, H., Lai, Z., Fu, X., De Angelis, C., Gong, Y., Gao, Z., Ruan, J., Jin, V. X., Marangoni, E., Montaudon, E., Glass, C. K., Li, W., Huang, T. H. M., Shao, Z. M., Schiff, R., ... Liu, Z. (2020). Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance. Nature Cell Biology, 22(6), 701-715. https://doi.org/10.1038/s41556-020-0514-z