Activation of Notch Signaling in a Xenograft Model of Brain Metastasis

  • Nam D
  • Jeon H
  • Kim S
 et al. 
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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 {gamma}-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.

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  • Do-Hyun Nam

  • Hye-Min Jeon

  • Shiyeon Kim

  • Mi Hyun Kim

  • Young-Ju Lee

  • Min Su Lee

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