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Sox2 promotes tamoxifen resistance in breast cancer cells

Marco Piva, Giacomo Domenici, Oihana Iriondo

    EMBO Molecular Medicine
    |November 2, 2013
    PubMed

    Insights

    Cancer stem cells drive tamoxifen resistance in breast cancer by activating Sox2 and Wnt signaling. Silencing Sox2 restores tamoxifen sensitivity, offering a potential therapeutic target.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • Therapy resistance is a major challenge in breast cancer treatment.
    • Cancer stem/progenitor cells are implicated in resistance to chemotherapy and radiotherapy.
    • The role of these cells in tamoxifen resistance remains to be fully elucidated.

    Purpose of the Study:

    • To investigate the role of cancer stem/progenitor cells in tamoxifen resistance.
    • To explore the involvement of the stem cell marker Sox2 and Wnt signaling pathway in this process.

    Main Methods:

    • Development and characterization of tamoxifen-resistant breast cancer cells.
    • Gene silencing (SOX2) and ectopic expression of Sox2.
    • Gene expression profiling and pathway analysis (Wnt signaling).
    • In vitro and in vivo sensitivity assays.
    • Analysis of Sox2 expression in patient tumor samples.

    Main Results:

    • Tamoxifen-resistant cells showed enrichment of stem/progenitor populations with high Sox2 expression.
    • SOX2 gene silencing decreased stem/progenitor cells and restored tamoxifen sensitivity.
    • Ectopic Sox2 expression reduced tamoxifen sensitivity both in vitro and in vivo.
    • Sox2-expressing cells exhibited activated Wnt signaling, and Wnt inhibition sensitized resistant cells to tamoxifen.
    • Elevated Sox2 levels were observed in patients with endocrine therapy failure.

    Conclusions:

    • Sox2 drives tamoxifen resistance in breast cancer stem/progenitor cells.
    • This resistance is mediated through the activation of the Wnt signaling pathway.
    • Targeting Sox2 and Wnt signaling may represent a novel therapeutic strategy for overcoming tamoxifen resistance.

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