British journal of cancer · 2026
Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis.
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Riggio Alessandra I, Sweeney Kerri, Shaw Robin, Lawlor Amy, Khan Adiba, Ferrari Nicola, Anand Jayanthi, Galbraith Laura Ca, Gilroy Kathryn, Bull Courtney, Young Alex L, Athineos Dimitris, Hall Holly, Ghaffar Farah, Hughes Mark, Mitchell Claire A, Mitchell Louise, Nixon Colin, Adams Peter D, Roberts Edward W, Miller Crispin J, Dunne Philip D, Campbell Kirsteen J, Cameron Ewan R, Blyth Karen
Аннотация
INTRODUCTION: The genes encoding RUNX1 and its binding partner CBFβ are recurrently reported to be mutated in breast cancer, a major cause of mortality in women worldwide. However, the functional role for these proteins remains unproven.
METHODS: The putative tumour suppressor role of Runx1 was investigated in genetic mouse models of breast cancer. Stem cell assays, immunohistochemistry and RNAseq analyses were applied to study biological and molecular mechanisms.
RESULTS: Runx1 loss of function leads to accelerated disease onset and tumour development in breast cancer models. Combined deletion of Runx1 and Runx2 further resulted in mammary cells becoming exquisitely sensitive to WNT-driven transformation, with expedited emergence of multiple tumours. Runx1 ablation induces a stem cell-like phenotype in mammary epithelial cells, whilst transcriptomic analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co-deleted. Altered Runx expression in the mammary epithelium also drove alterations in the tumour immune microenvironment, with changes to neutrophil and macrophage populations.
CONCLUSIONS: Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Combined Runx1 and Runx2 loss dramatically accelerates disease progression suggesting that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.
METHODS: The putative tumour suppressor role of Runx1 was investigated in genetic mouse models of breast cancer. Stem cell assays, immunohistochemistry and RNAseq analyses were applied to study biological and molecular mechanisms.
RESULTS: Runx1 loss of function leads to accelerated disease onset and tumour development in breast cancer models. Combined deletion of Runx1 and Runx2 further resulted in mammary cells becoming exquisitely sensitive to WNT-driven transformation, with expedited emergence of multiple tumours. Runx1 ablation induces a stem cell-like phenotype in mammary epithelial cells, whilst transcriptomic analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co-deleted. Altered Runx expression in the mammary epithelium also drove alterations in the tumour immune microenvironment, with changes to neutrophil and macrophage populations.
CONCLUSIONS: Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Combined Runx1 and Runx2 loss dramatically accelerates disease progression suggesting that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.