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

JaneD Holland, B. Györffy, Regina Vogel, Klaus Eckert, Giovanni Valenti, Liang Fang, Philipp Lohneis, Sefer Elezkurtaj, Ulrike Ziebold, Walter Birchmeier

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1214-1227
Number of pages14
JournalCell Reports
Volume5
Issue number5
DOIs
Publication statusPublished - Dec 12 2013

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Catenins
Tumors
Breast Neoplasms
Estrogen Receptors
Neoplasms
Genes
Chemical activation
Chemokine CXCL12
Oncology
Chemotherapy
Human Mammary Glands
Chemokines
Therapeutics
Cells
Control systems
Drug Therapy
Survival
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome. / Holland, JaneD; Györffy, B.; Vogel, Regina; Eckert, Klaus; Valenti, Giovanni; Fang, Liang; Lohneis, Philipp; Elezkurtaj, Sefer; Ziebold, Ulrike; Birchmeier, Walter.

In: Cell Reports, Vol. 5, No. 5, 12.12.2013, p. 1214-1227.

Research output: Contribution to journalArticle

Holland, J, Györffy, B, Vogel, R, Eckert, K, Valenti, G, Fang, L, Lohneis, P, Elezkurtaj, S, Ziebold, U & Birchmeier, W 2013, 'Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome', Cell Reports, vol. 5, no. 5, pp. 1214-1227. https://doi.org/10.1016/j.celrep.2013.11.001
Holland, JaneD ; Györffy, B. ; Vogel, Regina ; Eckert, Klaus ; Valenti, Giovanni ; Fang, Liang ; Lohneis, Philipp ; Elezkurtaj, Sefer ; Ziebold, Ulrike ; Birchmeier, Walter. / Combined Wnt/β-Catenin, Met, and CXCL12/CXCR4 Signals Characterize Basal Breast Cancer and Predict Disease Outcome. In: Cell Reports. 2013 ; Vol. 5, No. 5. pp. 1214-1227.
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