title: Stable expression of human VDR in murine VDR-null cells recapitulates vitamin D mediated anti-cancer signaling.
abstract: Mammary tumor cells derived from vitamin D receptor (VDR) knock-out (KO) mice were engineered to stably express wild-type (WT) or mutated VDR for characterization of the mechanisms by which 1,25-dihydroxyvitamin D (1,25D), the VDR ligand, mediates growth regulation. Although KO cells were completely resistant to 1,25D, introduction of WT human VDR restored gene expression and growth inhibition in response to 1,25D and a variety of structural analogs. Pdgfb, Vegfa, and Nfkbi were identified as genomic targets of both human and murine VDR signaling in this cell model. KO cells expressing hVDRs containing point mutations (W286R, R274L) that reduce or abolish ligand binding did not exhibit changes in gene expression or growth in response to physiological doses of 1,25D but did respond to higher doses and more potent analogs. KO cells expressing hVDR with the G46D point mutation, which abrogates VDR binding to DR3 response elements, exhibited partial growth inhibition in response to 1,25D and synthetic vitamin D analogs, providing proof of principle that VDR signaling through alternative genomic or non-genomic mechanisms contributes to vitamin D mediated growth effects in transformed cells. We conclude that the 1,25D-VDR signaling axis that triggers anti-cancer effects is highly conserved between the murine and human systems despite differences in VDR protein, cofactors, and target genes and that these actions are not solely mediated via canonical VDRE signaling.
authors.affiliation: Cancer Research Center, University at Albany, Rensselaer, New York.
authors.forename: Meggan E
authors.initials: ME
authors.lastname: Keith
authors.forename: Erika
authors.initials: E
authors.lastname: LaPorta
authors.forename: JoEllen
authors.initials: J
authors.lastname: Welsh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D
keywords: breast cancer; genomic; non-genomic; vitamin D; vitamin D analog