Sox2 promotes tamoxifen resistance in breast cancer cells

Marco Piva, Giacomo Domenici, Oihana Iriondo, Miriam Rábano, Bruno M Simões, Valentine Comaills, Inmaculada Barredo, Jose A. López-Ruiz, Ignacio Zabalza, Robert Kypta, Maria D M Vivanco

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells. © 2013 The Authors.
    Original languageEnglish
    Pages (from-to)66-79
    Number of pages13
    JournalEMBO Molecular Medicine
    Volume6
    Issue number1
    DOIs
    Publication statusPublished - Jan 2014

    Keywords

    • Breast cancer
    • Sox2
    • Stem cells
    • Tamoxifen resistance
    • Wnt signalling

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