title: Loss of vitamin D receptor signaling from the mammary epithelium or adipose tissue alters pubertal glandular development.
abstract: Vitamin D₃ receptor (VDR) signaling within the mammary gland regulates various postnatal stages of glandular development, including puberty, pregnancy, involution, and tumorigenesis. Previous studies have shown that vitamin D₃ treatment induces cell-autonomous growth inhibition and differentiation of mammary epithelial cells in culture. Furthermore, mammary adipose tissue serves as a depot for vitamin D₃ storage, and both epithelial cells and adipocytes are capable of bioactivating vitamin D₃. Despite the pervasiveness of VDR in mammary tissue, individual contributions of epithelial cells and adipocytes, as well as the VDR-regulated cross-talk between these two cell types during pubertal mammary development, have yet to be investigated. To assess the cell-type specific effect of VDR signaling during pubertal mammary development, novel mouse models with mammary epithelial- or adipocyte-specific loss of VDR were generated. Interestingly, loss of VDR in either cellular compartment accelerated ductal morphogenesis with increased epithelial cell proliferation and decreased apoptosis within terminal end buds. Conversely, VDR signaling specifically in the mammary epithelium modulated hormone-induced alveolar growth, as ablation of VDR in this cell type resulted in precocious alveolar development. In examining cellular cross-talk ex vivo, we show that ligand-dependent VDR signaling in adipocytes significantly inhibits mammary epithelial cell growth in part through the vitamin D₃-dependent production of the cytokine IL-6. Collectively, these studies delineate independent roles for vitamin D₃-dependent VDR signaling in mammary adipocytes and epithelial cells in controlling pubertal mammary gland development.
authors.affiliation: Departments of Environmental Health and.
authors.forename: Abby L
authors.initials: AL
authors.lastname: Johnson
authors.affiliation: Departments of Environmental Health and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Glendon M
authors.initials: GM
authors.lastname: Zinser
authors.affiliation: Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio susan.waltz@uc.edu.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
mesh_terms: D052438:Adipocytes, White / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism; D003433:Crosses, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012741:Sexual Maturation; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D046509:Tissue Culture Techniques
chemical_list: D015850:Interleukin-6; D018167:Receptors, Calcitriol; C577686:interleukin-6, mouse; D002762:Cholecalciferol
keywords: cell cross-talk; mammary adipocyte; mammary epithelium; mammary gland development; paracrine signaling; vitamin D receptor