Kerri Sweeney¹, Alessandra Riggio¹, Nicola Ferrari¹, Robin Shaw¹, Kathryn Gilroy¹, Colin Nixon¹, Farah Hughes¹, Peter Adams², Ewan Cameron³, Karen Blyth¹
RUNX1 has previously been shown to have both tumour-suppressive and oncogenic roles, depending on the context. For example, RUNX1 function is commonly lost in various haematological malignancies but appears to act as a dominant oncogene in some subtypes of leukaemia. Similarly in breast cancer, the subtype appears to have a significant impact whereby ER-positive breast cancers often have RUNX1 mutations with associated loss of function, yet RUNX1 expression in the triple-negative (ER-/PR-/HER2-) subtype has been correlated with poor outcome in patients. We present definitive in vivo evidence of RUNX1 acting to restrict tumour development in two independent preclinical models of breast cancer (driven by PyMT and WNT signalling, respectively) in which conditional loss of Runx1 results in early tumour onset and increased tumour burden. We are currently exploring the mechanisms behind the tumour suppressive functions of RUNX1, with a particular focus on the transcriptional alterations that are initiated upon deleting this transcription factor complex. CRISPR/Cas9-mediated deletion of RUNX1 in the HC11 mammary cell line has revealed that loss of RUNX1 drives mammary cell stemness in mammosphere assays and colony forming assays. Loss of RUNX1 function also appears to enhance the stemness-promoting effects of Wnt3a-treatment in the 3D context. Conversely, ectopic expression of RUNX1 in these cells decreases mammosphere and colony formation capabilities, and dampens Wnt-enhanced stemness.