Tumour specific HORMAD1 expression perturbs mitotic arrest and drives sensitivity to mitotic kinase inhibitors
HORMAD1 expression is usually restricted to germ-line cells but is also aberrantly expressed in 60% of triple-negative breast cancers (TNBCs), where it is bi-modally expressed and associated with genomic instability. Here, we show that out-of-context HORMAD1 expression in mitotic cells perturbs mitotic arrest and generates aneuploidy. These phenotypes are caused by out-of-context HORMAD1 expression driving a weakening of the spindle assembly checkpoint (SAC) and/or in kinetochore-microtubule error correction. These mitotic effects of HORMAD1 are MAD2L1-independent, but instead caused by a HORMAD1/Aurora B interaction and defective Aurora B/INCENP signalling. Consistent with this mechanism, aberrant HORMAD1 expression causes sensitivity to MPS1, Aurora B or BUB1 inhibitors currently being investigated as cancer treatments. Our data suggests how out-of-context expression of a meiotic gene imparts genomic instability upon tumour cells and also identifies several associated dependencies as mechanism-based therapeutic targets for a large, biomarker-defined, subset of cancers.
Authors
- Chiara Marcozzi (ORCID: https://orcid.org/0000-0003-0038-5556)
- Nino Iakobachvili (ORCID: https://orcid.org/0000-0003-0797-2665)
- Sarmi Nath (ORCID: https://orcid.org/0000-0002-8302-7094)
- Kathryn Davidson (ORCID: https://orcid.org/0000-0002-8844-2246)
- Nadja D’Uonno (ORCID: https://orcid.org/0009-0008-5585-7083)
- Ioannis Roxanis (ORCID: https://orcid.org/0000-0002-9920-514X)
- Ruifang Lu (ORCID: https://orcid.org/0009-0001-0935-6447)
- Jonathon Pines (ORCID: https://orcid.org/0000-0002-5227-6004)
- Jelmar Quist (ORCID: https://orcid.org/0000-0003-3071-3776)
- Luke Hitchen
- Dragomir B. Krastev (ORCID: https://orcid.org/0000-0003-4298-7272)
- Valeria Amodeo (ORCID: https://orcid.org/0000-0001-6905-6713)
- Riccardo Ferro (ORCID: https://orcid.org/0000-0001-6532-4856)
- Daniel Weekes (ORCID: https://orcid.org/0000-0001-8083-7617)
- Gabriel Kollárovič (ORCID: https://orcid.org/0000-0002-3159-7781)
- Stephen J. Pettitt (ORCID: https://orcid.org/0000-0003-3313-3857)
- Mercedes Pardo Calvo
- Chris Starling
- Blanca Navarro-Llinas
- Alexia Martin
- Alexandra Carroll
- Nicolae Balan
- Andrew N. J. Tutt
- Harriet Kemp
- Christopher J. Lord
- Anita Grigoriadis
- Jyoti Choudhary
- Ricarda M. Hoffmann
- Richard Bayliss
- Syed Haider
- Marieke Otten
- Jennifer Trendell
- Lu Yu
- Callum Walker
- Ilhan Rahman
Institutions
- University of Leeds (GB)
- Institute of Cancer Research (GB)
- King's College London (GB)
- Breast Cancer Now (GB)
- Institute of Structural and Molecular Biology (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1038/s41467-026-69561-3
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Breast Cancer Research Foundation
- AstraZeneca
- Merck KGaA
- Wellcome Trust
- Cancer Research UK
- Breast Cancer Research Trust
- University of Warwick
- University of California, San Diego