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

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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 ≤ 0.005; fold change ≥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.

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Acknowledgments

The authors would like to thank members of the Reedijk Lab for valuable advice and support. This study was supported by funds to M.R. from the Canadian Breast Cancer Foundation. Analyses were performed using BRB-ArrayTools developed by Dr. Richard Simon and BRB-ArrayTools Development Team.

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Authors and Affiliations

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

    Brenda Cohen, Mamiko Shimizu, Julia Izrailit & Michael Reedijk

  2. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Julia Izrailit & Michael Reedijk

  3. Campbell Family Institute for Breast Cancer Research, University Health Network, MaRs Centre, Toronto, Canada

    Nancy F. L. Ng, Yuri Buchman & James G. Pan

  4. Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    Judy Dering

  5. Department of Surgical Oncology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 3-130, Toronto, ON, M5G-2M9, Canada

    Michael Reedijk

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  1. Brenda Cohen
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  2. Mamiko Shimizu
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Correspondence to Michael Reedijk.

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Cohen, B., Shimizu, M., Izrailit, J. et al. Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Res Treat 123, 113–124 (2010). https://doi.org/10.1007/s10549-009-0621-9

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  • DOI: https://doi.org/10.1007/s10549-009-0621-9

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