Abstract
We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (P<0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27Kip1 and p21Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Line, Tumor
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Cell Proliferation*
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Chromones / pharmacology
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27
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Enzyme Inhibitors / pharmacology
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Female
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Humans
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Ki-67 Antigen / metabolism
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Membrane Proteins
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins
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Signal Transduction / drug effects
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Transcription, Genetic
Substances
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CDKN1A protein, human
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CDKN1B protein, human
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Cell Adhesion Molecules
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Chromones
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Intracellular Signaling Peptides and Proteins
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Ki-67 Antigen
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MTDH protein, human
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Membrane Proteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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RNA-Binding Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proto-Oncogene Proteins c-akt