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      Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition

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          Abstract

          Tumors comprise cancer stem cells (CSCs) and their heterogeneous progeny within a stromal microenvironment. In response to transforming growth factor–β (TGF-β), epithelial and carcinoma cells undergo a partial or complete epithelial-mesenchymal transition (EMT), which contributes to cancer progression. This process is seen as reversible because cells revert to an epithelial phenotype upon TGF-β removal. However, we found that prolonged TGF-β exposure, mimicking the state of in vivo carcinomas, promotes stable EMT in mammary epithelial and carcinoma cells, in contrast to the reversible EMT induced by a shorter exposure. The stabilized EMT was accompanied by stably enhanced stem cell generation and anticancer drug resistance. Furthermore, prolonged TGF-β exposure enhanced mammalian target of rapamycin (mTOR) signaling. A bitopic mTOR inhibitor repressed CSC generation, anchorage independence, cell survival, and chemoresistance and efficiently inhibited tumorigenesis in mice. These results reveal a role for mTOR in the stabilization of stemness and drug resistance of breast cancer cells and position mTOR inhibition as a treatment strategy to target CSCs.

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          Author and article information

          Journal
          Science Signaling
          Sci. Signal.
          American Association for the Advancement of Science (AAAS)
          1945-0877
          1937-9145
          February 26 2019
          February 26 2019
          February 26 2019
          February 26 2019
          : 12
          : 570
          : eaau8544
          Article
          10.1126/scisignal.aau8544
          6746178
          30808819
          b6e40ab6-519c-4784-8013-baea0849d16d
          © 2019

          http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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