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The role of proto-oncogene fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression

Academic Article
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Overview

authors

  • Luo, Y. P.
  • Zhou, H.
  • Krueger, J.
  • Kaplan, C.
  • Liao, D.
  • Markowitz, D.
  • Liu, C.
  • Chen, T.
  • Chuang, T. H.
  • Xiang, R.
  • Reisfeld, Ralph

publication date

  • February 2010

journal

  • Oncogene  Journal

abstract

  • A growing body of evidence indicates that interactions between neoplastic cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are crucial in promoting tumor cell invasion and progression. Macrophages have an ambiguous role in these processes as this M1 phenotype correlates with tumoricidal capacity, whereas TAMs of M2 phenotype exert tumor-promoting effects. In this study, we provide evidence that interactions between mouse breast tumor cells and TAMs remodel the TME, leading to the upregulation of Fra-1, a member of the FOS family of transcription factor. In turn, this proto-oncogene initiates activation of the IL-6/JAK/Stat3 signaling pathway. This creates a malignant switch in breast tumor cells, leading to increased release of proangiogenic factors MMP-9, vascular endothelial growth factor and transforming growth factor-beta from tumor cells and intensified invasion and progression of breast cancer. Proof of the concept for the crucial role played by transcription factor Fra-1 in regulating these processes was established by specific knockdown of Fra-1 with small interfering RNA, which resulted in a marked suppression of tumor cell invasion, angiogenesis and metastasis in a mouse breast cancer model. Such a strategy could eventually lead to future efficacious treatments of metastatic breast cancer.

subject areas

  • Animals
  • Blotting, Western
  • Breast Neoplasms
  • Cell Communication
  • Cell Separation
  • Disease Progression
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Macrophages
  • Mice
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic
  • Proto-Oncogene Proteins c-fos
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
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Research

keywords

  • Fra-1
  • IL-6/JAK/Stat3 signaling pathway
  • tumor microenvironment
  • tumor-associated macrophages
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Identity

PubMed Central ID

  • PMC3032566

International Standard Serial Number (ISSN)

  • 0950-9232

Digital Object Identifier (DOI)

  • 10.1038/onc.2009.308

PubMed ID

  • 19966854
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Additional Document Info

start page

  • 662

end page

  • 673

volume

  • 29

issue

  • 5

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