Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers

Cell Cycle. 2012 Jan 15;11(2):367-76. doi: 10.4161/cc.11.2.18813. Epub 2012 Jan 15.


A distinct group of breast cancers, called "basal" or "triple-negative" (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin's effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin's efficacy in the clinical setting.

MeSH terms

  • Aminosalicylic Acids / pharmacology
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Benzenesulfonates / pharmacology
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Drug Synergism
  • Female
  • Humans
  • Metformin / pharmacology*
  • Receptors, Steroid / metabolism*
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism


  • Aminosalicylic Acids
  • Antimetabolites, Antineoplastic
  • Apoptosis Regulatory Proteins
  • Benzenesulfonates
  • NSC 74859
  • Receptors, Steroid
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Metformin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases