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Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation

Peiguo Shi1,2, Wenjing Liu1,3, Tala4

  • 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.

Cell Discovery
|May 9, 2017
PubMed

Insights

Metformin, a diabetes drug, reduces triple-negative breast cancer (TNBC) stem cells by inhibiting the PKA-GSK3β-KLF5 pathway. This targeted approach offers potential for new TNBC therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) lacks targeted therapies and has a poor prognosis.
  • Metformin, a type 2 diabetes drug, shows potential for targeting cancer stem cells.
  • The precise mechanism of metformin's action in TNBC remains unclear.

Purpose of the Study:

  • To investigate the efficacy and mechanism of metformin in suppressing TNBC stem cells.
  • To elucidate the role of Krüppel-like factor 5 (KLF5) in metformin's anti-cancer effects.
  • To explore the involvement of the PKA-GSK3β signaling pathway in TNBC stem cell regulation.

Main Methods:

  • Treatment of TNBC cell lines with metformin.
  • Analysis of stem cell marker expression (KLF5, Nanog, FGF-BP1).
  • Investigation of protein phosphorylation and degradation pathways (PKA, GSK3β).
  • Correlation analysis in human TNBC patient samples.

Main Results:

  • Metformin decreased TNBC stem cell percentage by downregulating KLF5 and its targets (Nanog, FGF-BP1).
  • Metformin inhibited protein kinase A (PKA) activity, leading to GSK3β-mediated KLF5 phosphorylation and degradation.
  • PKA activators increased KLF5 expression, confirming the pathway's role.
  • Positive correlation observed between p-CREB, p-GSK3β, KLF5, and FGF-BP1 in human TNBC samples.

Conclusions:

  • Metformin suppresses TNBC stem cells via the PKA-GSK3β-KLF5 signaling pathway.
  • Targeting this pathway presents a potential therapeutic strategy for TNBC.
  • Further research is warranted to explore metformin's clinical application in TNBC treatment.
Keywords:
KLF5PKAmetforminstem cellstriple-negative breast cancer

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