Osteopontin gene expression determines spontaneous metastatic performance of orthotopic human breast cancer xenografts

Am J Pathol. 2007 Aug;171(2):682-92. doi: 10.2353/ajpath.2007.070232. Epub 2007 Jul 9.


A major problem in the therapeutic management of cancer is the growth of metastases in distant organs, but the genes orchestrating the process need to be identified for the rational design of new treatment. Here, we provide decisive experimental evidence demonstrating the causal involvement of a specific gene, osteopontin (OPN), in the pathogenesis of metastasis by human breast cancer cells and implicating some of its probable partners. Stable long-term depletion, or up-regulation, of OPN gene expression in a matched, isogenic pair of human breast cancer cell lines of differing metastatic proficiency reproducibly changed their ability to colonize distant organs. OPN down-regulation was achieved by transduction of the metastatic line with a DNA construct encoding a small hairpin RNA in a vector labeled with red fluorescent protein and resulted in a marked reduction of metastatic load (P < 0.01). Up-regulation of OPN in the negligibly metastatic line, with a green fluorescent protein-marked retroviral vector containing OPN cDNA driven by a strong promoter, resulted in heavy colonization of the lungs and lymph nodes (P < 0.005). The reciprocal changes in behavior of these matched cell lines cross-corroborate each other. Concomitant changes were seen in the expression of other metastasis-related genes in both modulated lines. The data indicate that therapeutic targeting of tumor OPN molecules could reset metastatically relevant gene networks, resulting in clinical benefit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Vectors / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lymphatic Metastasis
  • Mammary Neoplasms, Experimental / pathology*
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, SCID
  • Osteopontin / blood
  • Osteopontin / genetics
  • Osteopontin / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Transplantation, Heterologous
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism


  • Recombinant Fusion Proteins
  • Osteopontin
  • Green Fluorescent Proteins
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 2