Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity
Metrics: PDF 1106 views | HTML 1515 views | ?
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
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.