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Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
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Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers

Aarif Siddiqui1, Paradesi Naidu Gollavilli1,2, Annemarie Schwab1

  • 1Junior Research Group 1, IZKF, FAU Erlangen-Nürnberg, Erlangen, Germany.

Cell Death and Differentiation
|February 10, 2019
PubMed

Insights

Thymidylate synthase (TS) drives cancer cell de-differentiation and metastasis by boosting nucleotide metabolism. Targeting TS may offer new strategies for treating aggressive breast cancer (BC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Cancer cells often upregulate nucleotide metabolism (NM) to support proliferation.
  • The impact of elevated NM on tumor de-differentiation remains largely unknown.

Purpose of the Study:

  • Investigate the role of thymidylate synthase (TS), an NM enzyme, in cancer cell de-differentiation.
  • Explore the clinical significance of TS in breast cancer (BC).

Main Methods:

  • In vitro TS knockdown experiments in cancer cells.
  • RNA-sequencing (RNA-seq) for gene expression profiling.
  • In vivo metastasis assays.
  • Analysis of TS levels in patient breast cancer tissues.

Main Results:

  • TS knockdown promoted cell differentiation and reduced migration and sphere formation.
  • TS knockdown repressed epithelial-to-mesenchymal transition (EMT) signature genes.
  • TS deficiency led to increased invasion and metastasis in vivo, suggesting a partial EMT phenotype.
  • TS enzymatic activity fuels pyrimidine catabolism, maintaining the EMT/stem-like state.
  • Elevated TS levels in poorly differentiated and triple-negative BC correlate with worse prognosis.

Conclusions:

  • TS plays a critical role in cancer cell de-differentiation and metastasis.
  • TS is a potential therapeutic target for aggressive breast cancer.
  • Further research into NM's role in proliferation and differentiation is warranted for novel drug combinations.

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