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

• Published in: Breast cancer research and treatment Vol. 123; no. 1; pp. 113 - 124
• Main Authors: Cohen, Brenda, Shimizu, Mamiko, Izrailit, Julia, Ng, Nancy F. L, Buchman, Yuri, Pan, James G, Dering, Judy, Reedijk, Michael
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.08.2010; Springer US; Springer; Springer Nature B.V
• Subjects: Analysis; Biological and medical sciences; Blotting, Western; Breast cancer; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer research; Cancer therapies; Cell Line, Tumor; Chromatin Immunoprecipitation; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genes; Genomics; Gynecology. Andrology. Obstetrics; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; JAG1; Jagged-1 Protein; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Notch; Oligonucleotide Array Sequence Analysis; Oncology; Preclinical Study; Promoter Regions, Genetic - genetics; Proteins; 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; RNA; RNA, Small Interfering; Serrate-Jagged Proteins; Signal Transduction - genetics; Transfection; Triple negative; Tumors; Breast cancer; JAG1; Cyclin D1; Triple negative; Notch; Notch receptor; Breast disease; Targeting; Genomics; Etiopathogenesis; Malignant tumor; In vitro; Cell signaling; Mammary gland diseases; Signal transduction; Target; Gene; C-Onc gene; Genetics; Protooncogene; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-009-0621-9

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.