Oncotarget

Research Papers:

Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity

Abby L. Johnson, Glendon M. Zinser and Susan E. Waltz _

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Oncotarget. 2015; 6:16304-16320. https://doi.org/10.18632/oncotarget.4059

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Abstract

Abby L. Johnson1,2, Glendon M. Zinser1,2 and Susan E. Waltz2,3

1 Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA

2 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

3 Department of Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA

Correspondence to:

Susan E. Waltz, email:

Keywords: vitamin D3 receptor, ron, β-catenin, breast cancer

Received: January 28, 2015 Accepted: April 22, 2015 Published: May 10, 2015

Abstract

The Ron receptor is upregulated in human breast cancers and correlates with enhanced metastasis and reduced patient survival. Ron overexpression drives mammary tumorigenesis through direct β-catenin activation and augmented tumor cell proliferation, migration and invasion. Ron and β-catenin are also coordinately elevated in breast cancers. The vitamin D receptor (VDR) antagonizes β-catenin signaling. Herein, we examined mammary tumor onset and progression using a Ron-driven murine model of breast tumorigenesis crossed with VDR deficient mice. VDR ablation accelerated mammary tumor onset and led to tumors that exhibited a desmoplastic phenotype and enhanced metastases. Tumor levels of active β-catenin were markedly increased in the absence of VDR. In vitro, VDR activation in breast cancer cells reduced β-catenin activation and transcriptional activity leading to elevated expression of the extracellular Wnt inhibitor dickkopf-related protein 1, and a reduction in the interaction of β-catenin with the cyclin D1 promoter. Expression of a stabilized form or β-catenin ablated the protective effects of VDR activation.Collectively, these studies delineate a protective role for VDR signaling in Ron-induced mammary tumorigenesis through disruption of β-catenin activation.


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