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.