Mammary adipocytes bioactivate 25‐hydroxyvitamin D3 and signal via vitamin D3 receptor, modulating mammary epithelial cell growth

Abstract

The vitamin D(3) receptor (VDR) is present in all microenvironments of the breast, yet it is hypothesized to signal through the epithelium to regulate hormone induced growth and differentiation. However, the influence or contribution of the other microenvironments within the breast that express VDR, like the breast adipose tissue, are yet to be investigated. We hypothesized that the breast adipocytes express the signaling components necessary to participate in vitamin D(3) synthesis and signaling via VDR, modulating ductal epithelial cell growth and differentiation. We utilized human primary breast adipocytes and VDR wild type (WT) and knockout (KO) mice to address whether breast adipocytes participate in vitamin D(3) -induced growth regulation of the ductal epithelium. We report in this study that breast primary adipocytes express VDR, CYP27B1 (1α-hydroxylase, 1α-OHase), the enzyme that generates the biologically active VDR ligand, 1α,25-dihydroxyvitamin D(3) (1,25D(3) ), and CYP24 (24-hydroxylase, 24-OHase), a VDR-1,25D(3) induced target gene. Furthermore, the breast adipocytes participate in bioactivating 25-hydroxyvitamin D(3) (25D(3) ) to the active ligand, 1,25D(3) , and secreting it to the surrounding microenvironment. In support of this concept, we report that purified mammary ductal epithelial fragments (organoids) from VDR KO mice, co-cultured with WT breast adipocytes, were growth inhibited upon treatment with 25D(3) or 1,25D(3) compared to vehicle alone. Collectively, these results demonstrate that breast adipocytes bioactivate 25D(3) to 1,25D(3) , signal via VDR within the adipocytes, and release an inhibitory factor that regulates ductal epithelial cell growth, suggesting that breast adipose tissue contributes to vitamin D(3) -induced growth regulation of ductal epithelium.