The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer

Am J Pathol. 2009 Jul;175(1):66-73. doi: 10.2353/ajpath.2009.080948. Epub 2009 Jun 4.


The chemokine stromal cell-derived factor-1 (SDF-1) may function to attract CXCR4-expressing cancer cells to metastatic organs. We have previously demonstrated that low plasma SDF-1, a host-derived marker, increases distant metastatic risk in breast cancer. We therefore hypothesized that tumors overexpressing the SDF-1 receptor CXCR4 have an enhanced ability to metastasize in patients with low plasma SDF-1 levels. In this study, we determined the prognostic significance of activated CXCR4, or phosphorylated CXCR4 (p-CXCR4), and CXCR7, another receptor for SDF-1. Immunohistochemistry was performed on a tissue microarray built using 237 samples from the same cohort of patients for which we measured plasma SDF-1 levels. We found that the prognostic value of p-CXCR4 expression (hazard ratio or HR, 3.95; P = 0.004) was superior to total CXCR4 expression (HR, 3.20; P = 0.03). The rate of breast cancer-specific mortality was much higher in patients with both high p-CXCR4 expression and low plasma SDF-1 levels (HR, 5.96; P < 0.001) than either low plasma SDF-1 (HR, 3.59; P = 0.01) or high p-CXCR4 expression (HR, 3.83; P = 0.005) alone. The added prognostic value of low plasma SDF-1 was only effective in patients with high p-CXCR4 expression, and as such, provides clinical validation for modulation of the metastatic potential of tumor cells by an inherent host-derived metastatic risk factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / analysis*
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Chemokine CXCL12 / blood*
  • Female
  • Humans
  • Immunohistochemistry
  • Ligands
  • Neoplasm Invasiveness / genetics
  • Phosphorylation
  • Prognosis
  • Receptors, CXCR / biosynthesis
  • Receptors, CXCR / genetics
  • Receptors, CXCR4 / biosynthesis*
  • Receptors, CXCR4 / genetics
  • Risk Factors
  • Tissue Array Analysis


  • ACKR3 protein, human
  • Biomarkers, Tumor
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Ligands
  • Receptors, CXCR
  • Receptors, CXCR4