Abstract
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produces one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides insights into the cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer.
Highlights
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis
Each subtype is speculated to arise from a different cell of origin[4]; gaps in our understanding of the full spectrum of cellular heterogeneity and the distinct cell types that comprise the human breast epithelium hinder our ability to investigate their roles in cancer initiation and progression
We collected a cohort of reduction mammoplasties from age- and ethnicity-matched, post-pubertal and pre-menopausal females (Supplementary Data 1), and performed scRNAseq on purified breast epithelial cells, which were isolated from surrounding stromal cells using flow cytometry based on differential expression of CD49f and EpCAM16
Summary
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Based on comparative bulk expression analyses, these luminal progenitors may have increased propensity to give rise to triple negative breast cancers in patients with mutations in the BRCA1 gene[9] It remains to be determined if other distinct cell types exist within the breast epithelium and how these relate to the known subtypes of breast cancer. Advances in generation sequencing and microfluidic based handling of cells and reagents enable us to explore cellular heterogeneity on a single cell level and reconstruct lineage hierarchies using single-cell mRNA sequencing (scRNAseq)[10,11] This approach allows an unbiased analysis of the spectrum of heterogeneity within a population of cells, since it utilizes transcriptome reconstruction from individual cells. This approach allows an unbiased analysis of the spectrum of heterogeneity within a population of cells, since it utilizes transcriptome reconstruction from individual cells. scRNAseq has been successfully applied to understand the complex subpopulations in normal tissues such as lung[11] or brain[10] as well as in various cancers including melanoma[12], glioblastoma[13], and within circulating tumor cells from patients with pancreatic cancer[14]
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