Oncotarget

Research Papers:

Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Pradip De, Jennifer H. Carlson, Hui Wu, Adam Marcus, Brian Leyland-Jones and Nandini Dey _

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Oncotarget. 2016; 7:43124-43149. https://doi.org/10.18632/oncotarget.8988

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Abstract

Pradip De1,2, Jennifer H. Carlson1, Hui Wu3, Adam Marcus3, Brian Leyland-Jones1,2, Nandini Dey1,2

1Department of Molecular & Experimental Medicine, Avera Research Institute, Sioux Falls, SD, USA

2Department of Internal Medicine, SSOM, University of South Dakota, Sioux Falls, SD, USA

3Department of Hematology and Oncology, WCI, Emory University, Atlanta, GA, USA

Correspondence to:

Nandini Dey, email: nandini.dey@avera.org

Keywords: integrin-directed migration, matrigel-invasion, Wnt-pathway modulators, LWnt3ACM stimulation, brain-metastasis specific TNBC cells

Received: January 25, 2016    Accepted: April 05, 2016    Published: April 26, 2016

ABSTRACT

Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.


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