title: Combined Wnt/β-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome.
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.
authors.affiliation: 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.
authors.forename: Jane D
authors.initials: JD
authors.lastname: Holland
authors.affiliation: 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.
authors.forename: Balázs
authors.initials: B
authors.lastname: Györffy
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Vogel
authors.affiliation: Experimental Pharmacology & Oncology (EPO), Robert-Roessle-Strasse 10, 13122 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Eckert
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valenti
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.affiliation: Institute for Pathology, Charité Medical University, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lohneis
authors.affiliation: Institute for Pathology, Charité Medical University, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Sefer
authors.initials: S
authors.lastname: Elezkurtaj
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Ziebold
authors.affiliation: Department of Cancer Research, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Strasse 10, 13125 Berlin, Germany. Electronic address: wbirch@mdc-berlin.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C553307:HGF protein, mouse; D019718:Receptors, CXCR4; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met