Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer.
Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential. In IBC, E-cadherin is overexpressed and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer.
Silvera
Deborah
D
Department of Microbiology, New York University School of Medicine, New York, 10016, USA.
Arju
Rezina
R
Darvishian
Farbod
F
Levine
Paul H
PH
Zolfaghari
Ladan
L
Goldberg
Judith
J
Hochman
Tsivia
T
Formenti
Silvia C
SC
Schneider
Robert J
RJ
D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D010750:Phosphoproteins; D000095002:Delta Catenin