title: Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers.
abstract: 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.
authors.affiliation: Department of Pathology, University of Colorado Denver, Denver, CO, USA.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Deng
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Wang
authors.forename: Anlong
authors.initials: A
authors.lastname: Deng
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
authors.forename: Susan M
authors.initials: SM
authors.lastname: Edgerton
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
authors.forename: Reema
authors.initials: R
authors.lastname: Wahdan-Alaswad
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001557:Benzenesulfonates / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000636:Aminosalicylic Acids; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D001557:Benzenesulfonates; C520337:NSC 74859; D011987:Receptors, Steroid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases