Scholarlink

<p><i>HORMAD1</i> 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 <i>HORMAD1</i> expression in mitotic cells perturbs mitotic arrest and generates aneuploidy. These phenotypes are caused by out-of-context <i>HORMAD1</i> expression driving a weakening of the spindle assembly checkpoint (SAC) and/or in kinetochore-microtubule error correction. These mitotic effects of <i>HORMAD1</i> are MAD2L1-independent, but instead caused by a HORMAD1/Aurora B interaction and defective Aurora B/INCENP signalling. Consistent with this mechanism, aberrant <i>HORMAD1</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Tumour specific HORMAD1 expression perturbs mitotic arrest and drives sensitivity to mitotic kinase inhibitors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月11日

查看全文
  • Callum Walker,
  • Gabriel Kollarovic,
  • Daniel Weekes,
  • Jennifer Trendell,
  • Ricarda M. Hoffmann,
  • Alexia Martin,
  • Riccardo Ferro,
  • Blanca Navarro-Llinas,
  • Luke Hitchen,
  • Mercedes Pardo Calvo,
  • Nicolae Balan,
  • Harriet Kemp,
  • Alexandra Carroll,
  • Kathryn Davidson,
  • Sarmi Nath,
  • Nadja D’Uonno,
  • Ruifang Lu,
  • Chris Starling,
  • Marieke Otten,
  • Nino Iakobachvili,
  • Chiara Marcozzi,
  • Ilhan Rahman,
  • Jelmar Quist,
  • Lu Yu,
  • Dragomir B. Krastev,
  • Valeria Amodeo,
  • Ioannis Roxanis,
  • Anita Grigoriadis,
  • Richard Bayliss,
  • Jyoti Choudhary,
  • Syed Haider,
  • Jonathon Pines,
  • Stephen J. Pettitt,
  • Christopher J. Lord,
  • Andrew N. J. Tutt

摘要

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.