Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Cell. 2018 May 3;173(4):879-893.e13. doi: 10.1016/j.cell.2018.03.041. Epub 2018 Apr 19.


Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients.

Keywords: breast cancer genomics; cancer aneuploidy; chemotherapy; copy-number evolution; intratumor heterogeneity; single-cell sequencing; therapy resistance; triple-negative breast cancer; tumor evolution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Case-Control Studies
  • Cluster Analysis
  • DNA Copy Number Variations
  • Drug Resistance, Neoplasm / genetics*
  • Exome / genetics
  • Female
  • Gene Frequency
  • Genotype
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Neoadjuvant Therapy
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Single-Cell Analysis
  • Survival Analysis
  • Transcriptome
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology


  • Antineoplastic Agents