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Figure 1 | Breast Cancer Research

Figure 1

From: Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study

Figure 1

Proposed mechanism of action of metformin. (A) The potential mechanism(s) of antitumor action of metformin involves both direct (insulin-independent) and indirect (insulin-dependent) actions of the drug. The direct, insulin-independent effects of metformin involve activation of AMP-activated protein kinase (AMPK) in cancer cells via phosphorylation on Thr172 by liver kinase B1 (LKB1) and a subsequent reduction in mammalian target of rapamycin (mTOR) signaling, protein synthesis and cell proliferation. AMPK-independent actions of metformin may also contribute to its anticancer effects. The indirect, insulin-dependent effects are associated with reductions in circulating insulin levels mediated by inhibition of hepatic gluconeogenesis. The resulting decrease in insulin leads to reduced insulin receptor (IR)-mediated cancer cell signaling. (B) The results of the present study indicate that insulin-dependent effects of metformin are important in the clinical setting. Decreases in circulating insulin levels in metformin-treated patients, coupled with reductions in Akt (S473) and extracellular signal-regulated kinase 1/2 (ERK1/2; T202/Y204) phosphorylation in breast cancer cells, suggest reduced IR activation followed by decreases in phosphatidylinositol 3-kinase (PI3K) and Ras-mitogen-activated protein kinase (MAPK) signaling, cell proliferation and survival. MEK1/2, Mitogen-activated protein kinase kinase 1/2; mTORC1, Mammalian target of rapamycin complex 1; OCT1, Organic cation transporter 1.

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