A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer.
Translational regulation is critical in cancer development and progression. Translation sustains tumor growth and development of a tumor vasculature, a process known as angiogenesis, which is activated by hypoxia. Here we first demonstrate that a majority of large advanced breast cancers overexpress translation regulatory protein 4E-BP1 and initiation factor eIF4G. Using model animal and cell studies, we then show that overexpressed 4E-BP1 and eIF4G orchestrate a hypoxia-activated switch from cap-dependent to cap-independent mRNA translation that promotes increased tumor angiogenesis and growth at the level of selective mRNA translation. Elevated levels of 4E-BP1 trigger hypoxia inhibition of cap-dependent mRNA translation at high-oxygen levels and, with eIF4G, increase selective translation of mRNAs containing internal ribosome entry sites (IRESs) that include key proangiogenic, hypoxia, and survival mRNAs. The switch from cap-dependent to cap-independent mRNA translation facilitates tumor angiogenesis and hypoxia responses in animal models.
Braunstein
Steve
S
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Karpisheva
Ksenia
K
Pola
Carolina
C
Goldberg
Judith
J
Hochman
Tsivia
T
Yee
Herman
H
Cangiarella
Joan
J
Arju
Rezina
R
Formenti
Silvia C
SC
Schneider
Robert J
RJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D010750:Phosphoproteins; D012315:RNA Caps; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A