Combined Wnt/β-catenin, met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome


  • J.D. Holland
  • B. Györffy
  • R. Vogel
  • K. Eckert
  • G. Valenti
  • L. Fang
  • P. Lohneis
  • S. Elezkurtaj
  • U. Ziebold
  • W. Birchmeier


  • Cell Reports


  • Cell Rep 5 (5): 1214-1227


  • Prognosis for patients with estrogen-receptor (ER)-negative basal breast cancer is poor, and chemotherapy is currently the best therapeutic option. We have generated a compound-mutant mouse model combining the activation of {beta}-catenin and HGF (Wnt-Met signaling), which produced rapidly growing basal mammary gland tumors. We identified the chemokine system CXCL12/CXCR4 as a crucial driver of Wnt-Met tumors, given that compound-mutant mice also deficient in the CXCR4 gene were tumor resistant. Wnt-Met activation rapidly expanded a population of cancer-propagating cells, in which the two signaling systems control different functions, self-renewal and differentiation. Molecular therapy targeting Wnt, Met, and CXCR4 in mice significantly delayed tumor development. The expression of a Wnt-Met 322 gene signature was found to be predictive of poor survival of human patients with ER-negative breast cancers. Thus, targeting CXCR4 and its upstream activators, Wnt and Met, might provide an efficient strategy for breast cancer treatment.