title: Vitamin D3-dependent VDR signaling delays ron-mediated breast tumorigenesis through suppression of β-catenin activity.
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.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.|Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Johnson
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.|Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Glendon M
authors.initials: GM
authors.lastname: Zinser
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Department of Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002762:Cholecalciferol / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D002762:Cholecalciferol; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: breast cancer; ron; vitamin D3 receptor; β-catenin