Open Access Highly Accessed Research article

Wnt signaling in triple negative breast cancer is associated with metastasis

Nandini Dey12, Benjamin G Barwick5, Carlos S Moreno45, Maja Ordanic-Kodani10, Zhengjia Chen6, Gabriella Oprea-Ilies13, Weining Tang5, Charles Catzavelos117, Kimberly F Kerstann5, George W Sledge8, Mark Abramovitz129, Mark Bouzyk3, Pradip De12 and Brian R Leyland-Jones12*

Author Affiliations

1 Edith Sanford Breast Cancer, Sanford Research, 2301 E 60th Street N, Sioux Falls, SD 57104, USA

2 Department of Internal Medicine, University of South Dakota, Vermillion, SD 57069, USA

3 AKESOgen, Inc., Atlanta, GA 30071, USA

4 Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA

5 Winship Cancer Institute, Atlanta, GA 30322, USA

6 Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30022, USA

7 Department of Pathology, St. Mary’s Hospital, McGill University, Montreal, QC H3A 1G5, Canada

8 Indiana University Cancer Center, Indiana Cancer Pavilion, Indianapolis, IN 46202, USA

9 VM Institute of Research, Montréal, QC H3G 1L5, Canada

10 Current address: Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333, USA

11 Current address: Director of Pathology, Ville Marie Multidisciplinary Medical Centre, 1538, Sherbrooke Street W., Montréal, QC H3G 1L5, Canada

12 Current address: CHU Sainte-Justine Research Centre, Montréal, QC H3T 1C5, Canada

13 Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA

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BMC Cancer 2013, 13:537  doi:10.1186/1471-2407-13-537

Published: 10 November 2013

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.

Keywords:
Breast cancer; Triple negative; Wnt; FFPE; Microarray