The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis

Chengsen Xue, David Plieth, Christo Venkov, Carol Xu, Eric G. Neilson*

*Corresponding author for this work

Research output: Contribution to journalArticle

219 Scopus citations

Abstract

When carcinoma cells metastasize, they change their phenotype to enhance motility. Cells making this switch selectively express S100A4, a p53-associated, calcium-binding protein known in the fibroblast literature as fibroblast-specific protein-1 (FSP1). FSP1 normally acts as a conversion signal for the local formation of tissue fibroblasts by epithelial-mesenchymal transition. We describe here a novel connection between the process of fibroblast development and the acquisition of a metastatic phenotype in genetically engineered mice with mammary carcinoma. More frequent lung metastases were observed in naïve recipients given purified populations of green fluorescent protein (GFP)+ tumor cells harvested from PyV-mT x FSP1+/+.GFP F1 mice compared with GFP- tumor cells (P ≤ 0.01), where GFP expression is under the control of the FSP1 promoter. The expression of GFP in these metastases reversibly attenuates with the establishment of secondary tumor nodules. Reduced numbers of metastases were also observed in PyV-mT x FSP1GFP/GFP F1 mice carrying null alleles for FSP1 (P ≤ 0.04) and in PyV-mT x FSP1.ΔTK+ F1 mice rescued with nucleoside analogues while expressing thymidine kinase under the control of the FSP1 promoter (P ≤ 0.01). We propose that epithelial-mesenchymal transition associated with the expression of FSP1 in tumor cells has a functional role in determining the latency of tumor dispersion and may be a convenient therapeutic target for controlling a key initiating event in metastatic progression.

Original languageEnglish (US)
Pages (from-to)3386-3394
Number of pages9
JournalCancer Research
Volume63
Issue number12
StatePublished - Jun 15 2003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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