A single-cell atlas of the healthy breast tissues reveals clinically relevant clusters of breast epithelial cells

Cell Rep Med. 2021 Mar 16;2(3):100219. doi: 10.1016/j.xcrm.2021.100219.


Single-cell RNA sequencing (scRNA-seq) is an evolving technology used to elucidate the cellular architecture of adult organs. Previous scRNA-seq on breast tissue utilized reduction mammoplasty samples, which are often histologically abnormal. We report a rapid tissue collection/processing protocol to perform scRNA-seq of breast biopsies of healthy women and identify 23 breast epithelial cell clusters. Putative cell-of-origin signatures derived from these clusters are applied to analyze transcriptomes of ~3,000 breast cancers. Gene signatures derived from mature luminal cell clusters are enriched in ~68% of breast cancers, whereas a signature from a luminal progenitor cluster is enriched in ~20% of breast cancers. Overexpression of luminal progenitor cluster-derived signatures in HER2+, but not in other subtypes, is associated with unfavorable outcome. We identify TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts, and their expression analyses in >550 breast cancers enable prognostically relevant subclassification of ER+ breast cancers.

Keywords: breast cancer; cell of origin; epithelial cell clusters; normal breasts; single-cell analyses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Atlases as Topic
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Lineage / genetics*
  • Epithelial Cells / classification
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism
  • Prognosis
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction
  • Single-Cell Analysis / methods
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Survival Analysis
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism
  • Transcriptome


  • ESR1 protein, human
  • Estrogen Receptor alpha
  • PDK4 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • T-Box Domain Proteins
  • TBX3 protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2