Inflammatory breast cancer cells are constitutively adapted to hypoxia.
We recently showed that overexpression of translation initiation factor eIF4G partially drives the unusual pathological features of Inflammatory Breast Cancer (IBC), the most lethal form of primary breast cancer. IBC has the peculiar feature that, rather than develop as a solid tumor, it typically generates rapidly metastasizing tight clusters of cancer cells referred to as tumor cell emboli, consisting of cancer cells held together by increased membrane expression of E-cadherin. Overexpression of eIF4GI in IBC leads to a specific increase in the translation of internal ribosomal entry site (IRES) containing mRNAs, of which two encode key proteins involved in the pathological features of IBC. One of these mRNAs encodes p120 catenin, which mediates E-cadherin retention at the cell surface, and the other encodes VEGF, which accounts for high levels of IBC angiogenesis and resistance to hypoxia. Here we show that IBC cells have adapted to the persistent hypoxia they experience as tumor emboli, by reprogramming the protein synthesis machinery to constitutively translate mRNAs required for IBC cell survival during hypoxia, even under normal oxygen (normoxic) conditions. Thus, IBC cells have been able to behave as if they are continuously hypoxic even when they are not.
Silvera
Deborah
D
Department of Microbiology, New York University School of Medicine, New York, NY, USA.
Schneider
Robert J
RJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000378:metabolism; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D005260:Female; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D051177:Catenins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D010750:Phosphoproteins; D042461:Vascular Endothelial Growth Factor A