Oncogenic ESR1 fusions form chromatin-anchored condensates that remodel nuclear architecture

Abstract

Estrogen receptor (ESR1) fusions are recurrent drivers of endocrine-resistant breast cancer, yet their mechanisms of action remain poorly understood. Here, we show that ESR1-e6 fusion proteins, including ESR1-DAB2, ESR1-SOX9, and ESR1-YAP1, assemble into nuclear condensates across multiple cell types. Sequence analysis reveals that these fusions combine chromatin-targeting domains with increased intrinsic disorder, promoting multivalent interactions and phase separation. Live-cell imaging, fluorescence recovery after photobleaching, and mechanical perturbation demonstrate that condensates exhibit liquid-like properties, but progressively mature into stable, viscoelastic assemblies constrained by chromatin. Disruption of DNA binding abolishes condensate formation, indicating that chromatin engagement is essential for their assembly and organisation. ESR1 fusion condensates localise to chromatin-depleted regions, reduce nuclear stiffness, and promote chromatin decompaction, consistent with active remodelling of nuclear architecture. We propose that ESR1 fusions exploit phase separation to generate chromatin-anchored assemblies that reorganise the nuclear microenvironment, providing a physical framework through which ESR1 fusions may support sustained transcriptional activity, endocrine resistance and tumour progression.