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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Wnt signaling in triple negative breast cancer is associated with metastasis

Authors: Nandini Dey, Benjamin G Barwick, Carlos S Moreno, Maja Ordanic-Kodani, Zhengjia Chen, Gabriella Oprea-Ilies, Weining Tang, Charles Catzavelos, Kimberly F Kerstann, George W Sledge Jr., Mark Abramovitz, Mark Bouzyk, Pradip De, Brian R Leyland-Jones

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.

Methods

We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.

Results

The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.

Conclusion

These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
Appendix
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Metadata
Title
Wnt signaling in triple negative breast cancer is associated with metastasis
Authors
Nandini Dey
Benjamin G Barwick
Carlos S Moreno
Maja Ordanic-Kodani
Zhengjia Chen
Gabriella Oprea-Ilies
Weining Tang
Charles Catzavelos
Kimberly F Kerstann
George W Sledge Jr.
Mark Abramovitz
Mark Bouzyk
Pradip De
Brian R Leyland-Jones
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-537

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