Journal
SCIENCE SIGNALING
Volume 12, Issue 570, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aau8544
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Categories
Funding
- National Cancer Institute [RO1-CA63101, RO1-CA136690, R21CA164772, 5P30 CA082103, RO1CA210561]
- KAKENHI from Japan Society for the Promotion of Science (JSPS) [15H05774]
- NIH [P50 AA017072]
- Stand Up To Cancer Lung Cancer Dream Team
- Samuel Waxman Cancer Research Foundation
- Howard Hughes Medical Institute
- JSPS [16 K20974]
- Swiss National Science Foundation
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Tumors comprise cancer stem cells (CSCs) and their heterogeneous progeny within a stromal microenvironment. In response to transforming growth factor-beta (TGF-beta), 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-beta removal. However, we found that prolonged TGF-beta 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-beta 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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