Abstract
The Notch ligand, JAG1 is associated with breast cancer recurrence. Herein, we report on a genomics approach to elucidate mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines, we found that triple negative (TN; basal and mesenchymal ER-, PR-, and Her2-negative) lines express JAG1 at significantly higher levels than do HER2(+) or luminal (ER(+)) Her2(-) cell lines. In contrast to the luminal lines tested (T47D and MCF7), TN breast cancer cell lines (HCC1143 and MDA MB231) display high-level JAG1 expression and growth inhibition with RNA interference-induced JAG1 down-regulation. We used microarray profiling of TN tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes (P <or= 0.005; fold change >or=1.5). Among JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation reduces direct binding of Notch to the cyclin D1 promoter, reduced cyclin D1 expression and inhibition of cell cycle progression through the cyclin D1-dependant G1/S checkpoint. Furthermore, we show that cyclin D1 and JAG1 expression correlate in TN breast cancer expression datasets. These data suggest a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancers.
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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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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Cyclin D1 / genetics
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Cyclin D1 / metabolism*
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Female
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Gene Expression
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Gene Expression Regulation, Neoplastic*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / genetics
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RNA, Small Interfering
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / genetics
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Receptors, Estrogen / biosynthesis
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Receptors, Estrogen / genetics
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Receptors, Progesterone / biosynthesis
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Receptors, Progesterone / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Signal Transduction / genetics*
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Transfection
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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RNA, Small Interfering
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Receptors, Estrogen
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Receptors, Notch
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Receptors, Progesterone
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Serrate-Jagged Proteins
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Cyclin D1
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Receptor, ErbB-2