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

• DOI: 10.4161/cc.11.2.18813
• Publication Date: 2012-01-31T16:56:59Z
• Authors: Xin-Sheng Deng; Shuiliang Wang; Anlong Deng; Bolin Liu; Susan M. Edgerton; Stuart E. Lind; Reema Wahdan-Alaswad; Ann D. Thor
• Keywords: Growth inhibition

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