Decreased eIF3e/Int6 expression causes epithelial-to-mesenchymal transition in breast epithelial cells.
eIF3e/Int6 is a component of the multi-subunit eIF3 complex, which binds directly to the 40S ribosome to facilitate ribosome recruitment to mRNA and hence protein synthesis. Reduced expression of eIF3e/Int6 has been found in up to 37% of human breast cancers, and expression of a truncated mutant version of the mouse eIF3e/Int6 protein leads to malignant transformation of normal mammary cells. These findings suggest that eIF3e/Int6 is a tumor suppressor; however, a recent study has reported that a reduction of eIF3e/Int6 expression in breast cancer cells leads to reduced translation of oncogenes, suggesting that eIF3e/Int6 may in fact have an oncogenic role in breast cancer. To gain a better understanding of the role of eIF3e/Int6 in breast cancer, we have examined the effects of decreased eIF3e/Int6 expression in an immortalized breast epithelial cell line, MCF-10A. Surprisingly, we find that decreased expression of eIF3e/Int6 causes breast epithelial cells to undergo epithelial-to-mesenchymal transition (EMT). We show that EMT induced by a decrease in eIF3e/Int6 expression imparts invasive and migratory properties to breast epithelial cells, suggesting that regulation of EMT by eIF3e/Int6 may have an important role in breast cancer metastasis. Furthermore, we show that reduced eIF3e/Int6 expression in breast epithelial cells causes a specific increase in the expression of the key EMT regulators Snail1 and Zeb2, which occurs at both the transcriptional and post-transcriptional levels. Together, our data indicate a novel role of eIF3e/Int6 in the regulation of EMT in breast epithelial cells and support a tumor suppressor role of eIF3e/Int6.
Atlantic Cancer Research Institute, Hôtel-Dieu Pavilion, Moncton, New Brunswick, Canada.
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Gillis
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Lewis
D001483:Base Sequence; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2
D039621:Eukaryotic Initiation Factor-3; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2