Abstract
Expression of cyclin E proteolytic cleavage products, low-molecular weight cyclin E (LMW-E), is associated with poor clinical outcome in patients with breast cancer and it enhances tumorigenecity in mouse models. Here we report that LMW-E expression in human mammary epithelial cells induces an epithelial-to-mesenchymal transition phenotype, increases the CD44(hi)/CD24(lo) population, enhances mammosphere formation, and upregulates aldehyde dehydrogenase expression and activity. We also report that breast tumors expressing LMW-E have a higher proportion of CD44(hi)/CD24(lo) tumor cells as compared with tumors expressing only full-length cyclin E. In order to explore how LMW-E enriches cancer stem cells in breast tumors, we conducted a protein microarray analysis that identified the histone acetyltransferase (HAT) Hbo1 as a novel cyclin E/CDK2 substrate. The LMW-E/CDK2 complex phosphorylated Hbo1 at T88 without affecting its HAT activity. When coexpressed with LMW-E/CDK2, wild-type Hbo1 promoted enrichment of cancer stem-like cells (CSC), whereas the T88 Hbo1 mutant reversed the CSC phenotype. Finally, doxorubicin and salinomycin (a CSC-selective cytotoxic agent) synergized to kill cells expressing LMW-E, but not full-length cyclin E. Collectively, our results suggest that the heightened oncogenecity of LMW-E relates to its ability to promote CSC properties, supporting the design of therapeutic strategies to target this unique function.
©2013 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / pharmacology
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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CD24 Antigen / genetics
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CD24 Antigen / metabolism
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Cell Proliferation / drug effects
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Cyclin E / genetics
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Cyclin E / metabolism*
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Cyclin-Dependent Kinase 2 / genetics
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Cyclin-Dependent Kinase 2 / metabolism*
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Doxorubicin / pharmacology
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Drug Synergism
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Drug Therapy, Combination
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Epithelial-Mesenchymal Transition*
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Female
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Flow Cytometry
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Fluorescent Antibody Technique
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Histone Acetyltransferases / antagonists & inhibitors
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism*
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Immunoprecipitation
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Molecular Weight
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Phosphorylation
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Protein Array Analysis
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Pyrans / pharmacology
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
Substances
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Anti-Bacterial Agents
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Antibiotics, Antineoplastic
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CD24 Antigen
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Cyclin E
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Hyaluronan Receptors
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Pyrans
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RNA, Messenger
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RNA, Small Interfering
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salinomycin
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Doxorubicin
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Histone Acetyltransferases
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KAT7 protein, human
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CDK2 protein, human
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Cyclin-Dependent Kinase 2