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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Charissa Kim1, Ruli Gao2, Emi Sei2

  • 1Department of Genetics, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biological Sciences, UT MD Anderson Cancer Center, Houston, TX 77030, USA.

Cell
|April 24, 2018
PubMed

Insights

Chemotherapy resistance in triple-negative breast cancer (TNBC) arises from pre-existing resistant cell clones, not new genetic changes. These resistant genotypes are selected by treatment, while cells adapt their gene expression during chemotherapy.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Biology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype known for frequent chemotherapy resistance.
  • The origin of this resistance (pre-existing clones vs. new mutations) remains a critical unresolved question.

Purpose of the Study:

  • To investigate the mechanisms driving chemotherapy resistance in TNBC.
  • To differentiate between clonal selection and acquired genomic aberrations as causes of resistance.

Main Methods:

  • Longitudinal profiling of 20 TNBC patients undergoing neoadjuvant chemotherapy (NAC).
  • Application of bulk exome sequencing, single-cell DNA sequencing (900 cells), and single-cell RNA sequencing (6,862 cells).

Main Results:

  • Deep exome sequencing revealed clonal extinction in 10 patients and clone persistence in 10 patients post-NAC.
  • Single-cell analyses demonstrated that resistant genotypes were pre-existing and adaptively selected by NAC.
  • Transcriptional profiles were acquired through cellular reprogramming in response to chemotherapy.

Conclusions:

  • Chemotherapy resistance in TNBC is primarily driven by the adaptive selection of pre-existing resistant clones.
  • Cellular reprogramming and acquired transcriptional profiles contribute to treatment response and resistance in TNBC.
Keywords:
breast cancer genomicscancer aneuploidychemotherapycopy-number evolutionintratumor heterogeneitysingle-cell sequencingtherapy resistancetriple-negative breast cancertumor evolution

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