Regulation of mammary stem/progenitor cells by PTEN/Akt/β-catenin signaling

Hasan Korkaya, Amanda Paulson, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Marty Brown, Julie Dutcher, Shawn G. Clouthier, Max S. Wicha

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398 Scopus citations

Abstract

Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/β-catenin pathway through the phosphorylation of GSK3-β. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/β-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.

Original languageEnglish (US)
Article numbere1000121
JournalPLoS Biology
Volume7
Issue number6
DOIs
StatePublished - Jun 2009

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Korkaya, H., Paulson, A., Charafe-Jauffret, E., Ginestier, C., Brown, M., Dutcher, J., Clouthier, S. G., & Wicha, M. S. (2009). Regulation of mammary stem/progenitor cells by PTEN/Akt/β-catenin signaling. PLoS Biology, 7(6), [e1000121]. https://doi.org/10.1371/journal.pbio.1000121