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Activation of Notch Signaling in a Xenograft Model of Brain Metastasis

Authors' Affiliations: ¹ Neurosurgery and ² Plastic and Reconstructive Surgery, Samsung Medical Center and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, ³ Cell Growth Regulation Laboratory, Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, ⁴ Genomic Medicine Institute, MRC and Department of Biochemistry and Molecular Biology, ⁵ Cancer Research Institute, College of Medicine, ⁶ Biointelligence Laboratory, School of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea, and ⁷ Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Woong-Yang Park, Genomic Medicine Institute, MRC and Department of Biochemistry and Molecular Biology, College of Medicine, Seoul National University, 28 Yongondong, Chongnogu, Seoul 110-799, Republic of Korea. Phone: 82-2-740-8241; Fax: 82-2-744-4534; E-mail: wypark{at}snu.ac.kr or Sa Ik Bang, Department of Plastic and Reconstructive Surgery, Samsung Medical Center and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, 135-710, Republic of Korea. Phone: 82-2-3410-2215; Fax: 82-2-3410-0036; E-mail: sibang55{at}skku.edu.

Purpose: The potential of metastasis can be predicted from clinical features like tumor size, histologic grade, and gene expression patterns. We examined the whole-genome transcriptomic profile of a xenograft model of breast cancer to understand the characteristics of brain metastasis.

Experimental Design: Variants of the MDA-MB-435 cell were established from experimental brain metastases. The LvBr2 variant was isolated from lesions in a mouse injected in the left ventricle of the heart, and these cells were used for two cycles of injection into the internal carotid artery and selection of brain lesions, resulting in the Br4 variant. To characterize the different metastatic variants, we examined the gene expression profile of MDA-MB-435, LvBr2, and Br4 cells using microarrays.

Results: We could identify 2,016 differentially expressed genes in Br4 by using the F test. Various metastasis-related genes and a number of genes related to angiogenesis, migration, tumorigenesis, and cell cycle were differentially expressed by the Br4 cells. Notably, the Notch signaling pathway was activated in Br4, with increased Jag2 mRNA, activated Notch intracellular domain, and Notch intracellular domain/CLS promoter-luciferase activity. Br4 cells were more migratory and invasive than MDA-MB-435 cells in collagen and Matrigel Transwell assays, and the migration and invasion of Br4 cells were significantly inhibited by inactivation of Notch signaling using DAPT, a -secretase inhibitor, and RNA interference–mediated knockdown of Jagged 2 and Notch1.

Conclusions: Taken together, these results suggest that we have isolated variants of a human cancer cell line with enhanced brain metastatic properties, and the activation of Notch signaling might play a crucial role in brain metastasis.