Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer

Breast Cancer Res Treat. 2010 Aug;123(1):113-24. doi: 10.1007/s10549-009-0621-9. Epub 2009 Nov 14.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / genetics
  • RNA, Small Interfering
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / genetics
  • Receptors, Estrogen / biosynthesis
  • Receptors, Estrogen / genetics
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Receptors, Progesterone / biosynthesis
  • Receptors, Progesterone / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serrate-Jagged Proteins
  • Signal Transduction / genetics*
  • Transfection


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Receptors, Notch
  • Receptors, Progesterone
  • Serrate-Jagged Proteins
  • Cyclin D1
  • Receptor, ErbB-2