MassIVE MSV000083857

Partial Public PXD014015

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

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Description

Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, 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 ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, 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 [doi:10.25345/C54P79] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: BioID ; ER-alpha

Contact

Principal Investigators:
(in alphabetical order) 		Zhijie Liu, Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, United States of America
Submitting User: alexcampos

Publications

Bi M, Zhang Z, Jiang YZ, Xue P, Wang H, Lai Z, Fu X, De Angelis C, Gong Y, Gao Z, Ruan J, Jin VX, Marangoni E, Montaudon E, Glass CK, Li W, Huang TH, Shao ZM, Schiff R, Chen L, Liu Z.
Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance.
Nat. Cell Biol. Epub 2020 May 18.

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