Abstract

Abstract:

Characterising the hierarchy of mammary epithelial cells (MECs) and how they are regulated during adult development is important for understanding how breast cancer arises. Recently we used single-cell RNA sequencing (scRNAseq) to determine the gene expression profile of MECs across adult developmental stages. However, little is known about how during the early stages of breast cancer development, specific genetic aberrations impact the fate of MECs. In this talk I will describe our recent work where we identify the earliest cellular change in the mammary gland during triple negative breast cancer (TNBC) development. In this study, we examine the interplay between the TNBC oncogene, BCL11A , and the putative cell of origin, luminal progenitors. We demonstrate that the deletion of Bcl11a completely protects the Brca1/p53 TNBC mouse model from developing tumours. scRNAseq analysis of pre-cancerous tissue reveals that Bcl11a deletion fully reverses an aberrant differentiation behaviour of luminal progenitor cells. As such, our data demonstrates that Bcl11a is an essential oncogene in TNBC due to its critical role in enabling the cell of origin to aberrantly differentiate during early stages of tumour initiation. Finally, I will describe how we are expanding the use of single cell genomic approaches to understand changes in the Tumour Microenvironment (TME) during the various stages of tumour development. Collectively our data sheds light on the cellular changes during early stages of tumour development with potential implications for early detection and therapeutic intervention.