Cell Reports
Volume 5, Issue 5, 12 December 2013, Pages 1214-1227
Journal home page for Cell Reports

Article
Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome

https://doi.org/10.1016/j.celrep.2013.11.001Get rights and content
Under a Creative Commons license
open access

Highlights

  • Wnt, Met, and CXCR4 activation in mice induces ER-negative mammary gland tumors

  • The two signaling systems control different cancer-propagating cell functions

  • Combined pharmacological interference with Wnt, Met, and CXCR4 inhibits tumors

  • Murine tumor gene signatures predict poor outcome of ER-negative breast cancer patients

Summary

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 β-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.

Cited by (0)

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.