The Study Of Mammary Epithelial Cell Differentiation Dynamics And Breast Cancer Development By Single Cell RNA Sequencing Event

Event details

Characterising the hierarchy of mammary epithelial cells (MECs) and how they are regulated during adult development is important for understanding how breast cancer arises. In my talk I will discuss our recent work where we used single-cell RNA sequencing (scRNAseq) to determine the gene expression profile of MECs across four developmental stages; nulliparous, mid gestation, lactation and post involution. Our analysis of 23,184 cells identifies 15 clusters, few of which could be fully characterised by a single marker gene. We argue instead that the epithelial cells especially in the luminal compartment should rather be conceptualised as being part of a continuous spectrum of differentiation. Furthermore, our data supports the existence of a common luminal progenitor cell, giving rise to intermediate, restricted alveolar and hormone-sensing progenitors (Bach K. et al. Nat. Comm 2017). Understanding the biology of luminal progenitor cells is important given their proposed cell of origin role in triple negative breast cancer (TNBC). We then performed scRNAseq combined with genetic lineage tracing and in situ imaging to show that the transcription factor Bcl11a, a gene upregulated in TNBC, is expressed in long lived luminal progenitor cells that expand in response to MPA/DMBA mediated oncogenesis. Furthermore, we show that deletion of Bcl11a protects mice from developing tumours in the Brca1/p53 mouse model of TNBC. Single cell transcriptomics of pre-cancerous mammary epithelial cells revealed that the deletion fully reverses an aberrant differentiation behaviour of the luminal progenitor compartment associated with the Brca1/p53 mouse model. In summary, our results provide a global, unbiased view of adult mammary gland development and novel insights on how luminal progenitors contribute to TNBC initiation.