Bcl11a Marks Mammary Progenitor Cells and Promotes Early Cellular Changes Associated with TNBC by Recruiting Chd8

The transcription factor Bcl11a is an oncogene in triple negative breast cancer (TNBC), the subtype with the poorest prognostic outcome. Here we perform lineage-tracing combined with single-cell RNA-sequencing (scRNAseq) to show that Bcl11a is expressed in long lived luminal progenitor cells that expand in response to MPA/DMBA mediated oncogenesis. Moreover, we find that the deletion of Bcl11a protects mice from developing tumours in the Brca1/p53 mouse model of TNBC. scRNAseq of pre-cancerous mammary epithelial cells revealed that the deletion fully reverses an aberrant differentiation behaviour of the luminal progenitor compartment associated with Brca1 loss-of-function. Finally, we show that BCL11A interacts with and recruits the chromatin remodeller CHD8, which, we demonstrate is essential for mediating the oncogenic effects of BCL11A. In summary, BCL11A promotes early stages of TNBC via its formation of context specific protein interactions making them ideal candidate for drug development.