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

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

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  • 1Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Canada.

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.

PMID:
19915977
[PubMed - indexed for MEDLINE]
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