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.
Highlights
The Ron receptor tyrosine kinase, known as macrophage-stimulating 1 receptor (MST1R), is overexpressed in approximately 50% of human breast cancers [1] and is associated with increased metastasis and poor patient prognosis [2]
By 4 months of age almost all MMTV-Ron vitamin D receptor (VDR)+/+ and VDR-/- mice exhibited severely dilated, cystic acini similar to the mammary epithelium previously reported in MMTV-Ron induced tumorigenesis [13]
Previous studies have shown that Ron-mediated breast tumorigenesis requires β-catenin activation and transcriptional activity for tumor formation, cell proliferation and metastasis [13, 14]
Summary
The Ron receptor tyrosine kinase, known as macrophage-stimulating 1 receptor (MST1R), is overexpressed in approximately 50% of human breast cancers [1] and is associated with increased metastasis and poor patient prognosis [2]. In Ron expressing human breast cancer cell lines, T47D and ZR-75-1, activation of the Ron receptor increases cell proliferation, migration and invasion [1, 5]. In a model of breast cancer with targeted overexpression of Ron in the mammary epithelium, β-catenin was shown to be required for Ron-mediated mammary tumorigenesis [13, 14]. The β-catenin signaling axis has been shown to be upregulated in many human breast cancers and is associated with poor disease prognosis [15,16,17,18,19,20]. Understanding how perturbations in the Ronβ-catenin signaling axis affect the therapeutic response of breast cancers with a highly metastatic phenotype is critical for lessening the deaths associated with metastatic disease
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