Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis

Riggio, A. I.; Sweeney, K.; Shaw, R.; Khan, A.; Lawlor, A.; Ferrari, N.; Gilroy, K.; Bull, C.; Young, A.; Athineos, D.; Hall, H.; Ghaffar, F.; Nixon, C.; Adams, P.; Roberts, E.; Miller, C.; Dunne, P.; Campbell, K.; Cameron, E.; Blyth, K.

doi:10.1101/2025.03.16.643517

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bioRxiv · 10.1101/2025.03.16.643517

Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis

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Abstract

The genes encoding transcription factor RUNX1 and its binding partner CBFB have been reported to be mutated in human breast cancer. Here, we provide evidence that Runx1 loss of function results in accelerated disease onset and tumour development in mouse models of breast cancer, in keeping with a tumour suppressor role for RUNX1 in this disease setting. Combined deletion of Runx1 and the related family member Runx2 resulted in mammary epithelial cells becoming exquisitely sensitive to WNT-driven transformation, with the emergence of multiple tumours early in life. Clonogenic assays indicated that Runx1 ablation induced a stem cell like phenotype in mammary epithelial cells, whilst transcriptome analysis demonstrated activation of multiple oncogenic pathways, especially when Runx2 was co- deleted. Interestingly, altered Runx expression in the mammary epithelium also drove profound alterations in the tumour microenvironment, impacting the immune landscape. These results highlight that Runx1 restricts some forms of breast cancer and inhibits the full oncogenic potential of aberrant WNT signalling. Loss of Runx2 itself did not result in tumour promotion, yet the dramatic effects of combined Runx1 and Runx2 loss suggest that Runx2 can substitute for Runx1 in dampening the oncogenic effects of WNT signalling.

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Riggio, A. I., Sweeney, K., Shaw, R., Khan, A., Lawlor, A., Ferrari, N., Gilroy, K., Bull, C., Young, A., Athineos, D., Hall, H., Ghaffar, F., Nixon, C., Adams, P., Roberts, E., Miller, C., Dunne, P., Campbell, K., Cameron, E., Blyth, K.. 2025-03-17. Runx1 and Runx2 act in concert to suppress Wnt/β-catenin-driven mammary tumourigenesis. https://doi.org/10.1101/2025.03.16.643517

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