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Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective

Ryan J O Dowling, Saroj Niraula, Martin C Chang

    Breast Cancer Research : BCR
    |April 8, 2015
    PubMed
    Abstract

    Insights

    Metformin treatment reduced insulin receptor signaling in breast cancer patients, suggesting its potential as an anticancer therapy. This study identified key factors for patient sensitivity to metformin.

    Area of Science:

    • Oncology
    • Pharmacology
    • Endocrinology

    Background:

    • Metformin, an antidiabetic drug, shows promise as an anticancer agent through direct and indirect mechanisms.
    • Direct effects involve AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling inhibition.
    • Indirect effects are mediated by reduced circulating insulin and insulin receptor (IR) signaling.

    Purpose of the Study:

    • To investigate the in vivo effects of metformin on breast cancer cell signaling.
    • To identify factors influencing patient sensitivity to metformin-based therapies.

    Main Methods:

    • A neoadjuvant, single-arm "window of opportunity" clinical trial was conducted.
    • Non-diabetic women with breast cancer received metformin (500 mg three times daily) for at least two weeks before surgery.
    • Fasting blood and tumor samples were analyzed for glucose, insulin, and key cellular markers via immunohistochemistry.

    Main Results:

    • Metformin significantly decreased insulin receptor (IR) expression and phosphorylation of protein kinase B (PKB)/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in tumors.
    • Phosphorylation of AMPK and acetyl coenzyme A carboxylase also decreased significantly.
    • All tumors expressed organic cation transporter 1, with high expression in 90% of samples.

    Conclusions:

    • Reduced PKB/Akt and ERK1/2 phosphorylation, along with decreased insulin and IR levels, indicate the importance of insulin-dependent effects in the clinical efficacy of metformin.
    • These findings support metformin's potential anticancer benefits and highlight sensitivity markers for patient selection in metformin-based therapies.

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