RUNX/CBFβ transcription factor complexes promote the phenotypic plasticity of metastatic breast cancer cells

Abstract

Epithelial to mesenchymal transition (EMT) is a dynamic process that drives cancer cell plasticity and is thought to play a major role in metastasis. Here we show that the plasticity of metastatic breast cancer cells can be promoted by the activity of the RUNX transcription factors. We demonstrate that the RUNX co-regulator CBFβ is essential to maintain the mesenchymal phenotype of triple-negative breast cancer cells and that CBFβ-depleted cells undergo a mesenchymal to epithelial transition (MET) and re-organise into acini-like structures, reminiscent of those formed by epithelial breast cells. We subsequently show, using an inducible CBFβ system, that the MET can be reversed, thus demonstrating the plasticity of RUNX/CBFβ-mediated EMT. Moreover, the MET can be reversed by expression of the EMT transcription factor Slug whose expression is dependent on CBFβ, RUNX1 and RUNX2. Finally, we demonstrate that loss of CBFβ inhibits the ability of metastatic breast cancer cells to invade bone cell cultures and suppresses their ability to form bone metastases in vivo. Together our findings demonstrate that the RUNX/CBFβ complexes can determine the plasticity of the metastatic cancer cell phenotypes, suggesting that their regulation in different micro-environments may play a key role in the establishment of metastatic tumours.

Regulation of cancer stem cells in triple negative breast cancer

“…In TNBC, RUNX1 is an independent prognostic indicator of poor patient outcomes [ 170 ] . In TNBCSCs, RUNX transcription factors and their coregulator CBFβ promote phenotypic plasticity and are essential for maintaining of the mesenchymal, invasive phenotype [ 171 ] . RUNX1 was also recently shown to regulate R-Spondin 3 (RSPO3) in TNBCSCs, promoting EMT, motility and stemness [ 172 ] .…”