Journal
ONCOGENE
Volume 32, Issue 7, Pages 861-871Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.105
Keywords
elF4E; elF4A; PyMT mouse model; breast cancer; pulmonary metastasis
Funding
- Canadian Institutes of Health Research [MOP-89791, MOP-106530]
- CRC Chair in Molecular Oncology
- National Institutes of Health [GM-073855]
- Canadian Cancer Society Research Institute (CCSRI) [17099]
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Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome. Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo. Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, elF4E and elF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro. Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression. Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer. Targeting this pathway may be of therapeutic benefit. Oncogene (2013) 32, 861-871; doi:10.1038/onc.2012.105; published online 9 April 2012
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