Vitamin D3, a nutritionally modulated hormone, participates as a negative growth regulator of mammary gland development and transformation. However, the mechanism behind breast specific vitamin D3 synthesis, metabolism, and signaling to maintain glandular homeostasis and inhibit the onset of mammary transformation remains unknown. Our objective was to test the concept that vitamin D3 signaling in mammary adipose tissue contributes to the negative growth regulation of mammary epithelial cells. We hypothesized that the mammary adipose tissue bioactivates 25-hydroxyvitamin D3 [25(OH)D3] to the active metabolite, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and induces adipocyte Vitamin D3 Receptor (VDR) signaling along with paracrine secretion of 1,25(OH)2D3 to surrounding mammary epithelial cells to regulate growth of normal and transformed breast epithelial cells. We utilized mammary glands from VDR knockout (KO) and wild type (WT) mice for various procedures including ex vivo co-cultures with mammary epithelium and adipocytes, gene and protein expression assays, immunohistochemistry, and whole mount analysis. We discovered that breast adipocytes express essential signaling components of the vitamin D3 endocrine system and have the ability to bioactivate 25(OH)D3 to 1,25(OH)2D3 inducing mammary specific vitamin D3-responsive gene expression. Breast adipocytes likely participate to maintain localized vitamin D3 homeostasis and contribute to 1,25(OH)2D3-induced growth regulation of mammary epithelial cells in response to various hormonal stimulations, modulating mammary development and differentiation. Thus, our work suggests that breast adipose tissue serves as a vital endocrine mediator of Vitamin D3 signaling and offers a possible mechanism by which elevated 25(OH)D3 serum concentrations reduce the susceptibility to breast cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A57.
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