ESR1 fusion proteins in breast cancer: distinguishing oncogenic drivers from passenger events

Breast cancer is characterised by profound genetic heterogeneity, with oestrogen receptor alpha (ERα, encoded by ESR1) being a central driver in ~70% of cases. While point mutations in the ligand-binding domain of ESR1 are well recognised mediators of endocrine resistance, a growing body of evidence highlights ESR1 gene fusions as an emerging class of genomic alterations with important clinical implications. These rearrangements, predominantly arising from intrachromosomal events on chromosome 6, truncate the hormone-binding domain and fuse ESR1 with diverse partners, producing constitutively active chimeric proteins. Recurrent fusions such as ESR1-CCDC170, ESR1-YAP1, and ESR1-AKAP12 have been consistently associated with therapy resistance, metastatic progression, and poor clinical outcome, suggesting that they function as oncogenic drivers rather than incidental by-products of genomic instability. However, variability in oncogenic potential indicates that only a subset of fusions are biologically functional. Key determinants of functionality include reading-frame preservation, domain architecture, intrinsic disorder content, and the molecular features contributed by the partner gene, many of which encode transcription factors, signalling adaptors, or cytoskeletal regulators. Structural enrichment in intrinsically disordered regions and the potential for phase separation further implicate ESR1 fusions in the formation of aberrant transcriptional condensates that amplify ER signalling. Importantly, while many fusions are enriched in metastatic, treatment-resistant disease, a small number are present in treatment-naïve tumours, raising the possibility that some act as early drivers of oncogenesis. This review outlines the current knowledge on ESR1 fusions, evaluating their mechanisms and clinical relevance. Clarifying which ESR1 fusions act as true oncogenic drivers versus incidental events will be critical for refining diagnostics and informing future therapeutic development for oncofusion-driven cancers.