Complex rearrangements fuel ER+ and HER2+ breast tumours

Kathleen E. Houlahan, Lise Mangiante, Cristina Sotomayor-Vivas, Alvina Adimoelja, Seongyeol Park, Aziz Khan, Sophia J. Pribus, Zhicheng Ma, Jennifer L. Caswell-Jin and Christina Curtis ()
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Kathleen E. Houlahan: School of Medicine, Stanford University
Lise Mangiante: School of Medicine, Stanford University
Cristina Sotomayor-Vivas: School of Medicine, Stanford University
Alvina Adimoelja: School of Medicine, Stanford University
Seongyeol Park: School of Medicine, Stanford University
Aziz Khan: School of Medicine, Stanford University
Sophia J. Pribus: School of Medicine, Stanford University
Zhicheng Ma: School of Medicine, Stanford University
Jennifer L. Caswell-Jin: School of Medicine, Stanford University
Christina Curtis: School of Medicine, Stanford University

Nature, 2025, vol. 638, issue 8050, 510-518

Abstract: Abstract Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors—oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2)—is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER+ subtypes with increased risk of relapse decades after diagnosis1,2. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing. We demonstrate that breast tumours fall along a continuum constrained by three genomic archetypes. The ER+ high-risk integrative subgroup is characterized by complex focal amplifications, similar to HER2+ tumours, including cyclic extrachromosomal DNA amplifications induced by ER through R-loop formation and APOBEC3B-editing, which arise in pre-invasive lesions. By contrast, triple-negative tumours exhibit genome-wide instability and tandem duplications and are enriched for homologous repair deficiency-like signatures, whereas ER+ typical-risk tumours are largely genomically stable. These genomic archetypes, which replicate in an independent cohort of 2,659 primary tumours, are established early during tumorigenesis, sculpt the tumour microenvironment and are conserved in metastatic disease. These complex structural alterations contribute to replication stress and immune evasion, and persist throughout tumour evolution, unveiling potential vulnerabilities.

Date: 2025
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DOI: 10.1038/s41586-024-08377-x

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