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

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/beta-catenin pathway through the phosphorylation of GSK3-beta. 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/beta-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.
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Submitted on : Wednesday, June 13, 2012 - 11:30:35 AM
Last modification on : Thursday, August 8, 2019 - 1:15:25 AM
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Hasan Korkaya, Amanda Paulson, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Marty Brown, et al.. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.. PLoS Biology, Public Library of Science, 2009, 7 (6), pp.e1000121. ⟨10.1371/journal.pbio.1000121⟩. ⟨inserm-00707653⟩

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