Cyclin D1 Is a Direct Target of JAG-Mediated Notch Signaling in Breast Cancer.

Abstract

Abstract We have previously demonstrated that expression of the Notch ligand, JAG1 is associated with the basal breast cancer phenotype and disease 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. The TN breast cancer cell lines HCC1143 and MDA MB231, which express JAG1 and demonstrate growth inhibition with RNA interference-induced down-regulation of JAG1, were selected for further study. We used microarray profiling of tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes. Differentially expressed genes (p ≤ 0.005; fold change ≥ 1.5) were identified for further study. Among the JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation results in reduced cyclin D1 expression, reduced direct binding of Notch to the cyclin D1 promoter, and inhibition of cell cycle progression through the cyclin D1-dependant G1/S check-point. Furthermore, we show that cyclin D1 and JAG1 expression correlate in basal breast cancer expression data sets. These data suggest a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancer cells. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2150.