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Cell Rep. 2013 Dec 12;5(5):1214-27. doi: 10.1016/j.celrep.2013.11.001. Epub 2013 Nov 27.

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

Author information

1
Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany. Electronic address: jane.holland@mdc-berlin.de.
2
Research Laboratory of Pediatrics and Nephrology, Hungarian Academy of Sciences, Semmelweis University, Bókay u. 53-54, 1083 Budapest, Hungary; Institute for Pathology, Charité Medical University, Charitéplatz 1, 10117 Berlin, Germany.
3
Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
4
Experimental Pharmacology & Oncology (EPO), Robert-Roessle-Strasse 10, 13122 Berlin, Germany.
5
Institute for Pathology, Charité Medical University, Charitéplatz 1, 10117 Berlin, Germany.
6
Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany. Electronic address: wbirch@mdc-berlin.de.

Abstract

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.

PMID:
24290754
DOI:
10.1016/j.celrep.2013.11.001
[Indexed for MEDLINE]
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