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Thioguanine Induces Apoptosis in Triple-Negative Breast Cancer by Regulating PI3K-AKT Pathway

Daoyu Zhang1, Xinglan An1, Qi Li1

  • 1Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, First Hospital, Jilin University, Changchun, China.

Frontiers in Oncology
|November 16, 2020
PubMed

Insights

Triple-negative breast cancer (TNBC) is hard to treat. Researchers found the leukemia drug thioguanine (6-TG) inhibits TNBC growth by altering DNA methylation and activating apoptosis pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to limited targeted options and poor response to conventional treatments.
  • Effective screening strategies for chemotherapy drugs in TNBC remain underdeveloped.
  • Drug repositioning is an emerging approach gaining traction for identifying novel therapeutic agents.

Purpose of the Study:

  • To identify common molecular features between leukemia and TNBC using transcriptome analysis.
  • To investigate the anti-cancer potential of thioguanine (6-TG), a known leukemia drug, in TNBC.
  • To elucidate the molecular mechanisms underlying 6-TG's effects on TNBC cells.

Main Methods:

  • Comparative analysis of global transcriptome profiles from NCI60 data to identify shared features between leukemia and TNBC.
  • In vitro and in vivo experiments to evaluate the efficacy of 6-TG in TNBC models.
  • Investigation of the PI3K-AKT pathway, DNA methylation levels, and apoptosis-related gene expression in response to 6-TG treatment.

Main Results:

  • Multiple common transcriptome features were identified between leukemia and TNBC.
  • 6-TG demonstrated significant inhibition of TNBC cell proliferation and tumor progression.
  • 6-TG suppressed the PI3K-AKT pathway by downregulating PTEN DNA methylation and induced apoptosis via TSC1 activation and downregulation of methylation in DAXX, TNF, FADD, and CASP8.

Conclusions:

  • 6-TG exerts anti-tumor effects in TNBC through modulation of DNA methylation in genes critical for the PI3K-AKT and apoptosis pathways.
  • Transcriptome-based drug screening holds promise for advancing TNBC therapy and optimizing drug selection.
Keywords:
PI3K–AKTmethylationthioguaninetranscriptometriple-negative breast cancer

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