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A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells.

ABSTRACT: Breast cancer is the most common non-cutaneous malignancy in American women, and better preventative strategies are needed. Epidemiological and laboratory studies point to vitamin D3 as a promising chemopreventative agent for breast cancer. Vitamin D3 metabolites induce anti-proliferative effects in breast cancer cells in vitro and in vivo, but few studies have investigated their effects in normal mammary epithelial cells. We hypothesized that 1,25(OH)2D3, the metabolically active form of vitamin D3, is growth suppressive in normal mouse mammary epithelial cells. In addition, we have previously established a role for the cytokine interleukin-1 alpha (IL1?) in the anti-proliferative effects of 1,25(OH)2D3 in normal prostate cells, and so we hypothesized that IL1? is involved in the 1,25(OH)2D3 response in mammary cells. Evaluation of cell viability, clonogenicity, senescence, and induction of cell cycle regulators p21 and p27 supported an anti-proliferative role for 1,25(OH)2D3 in mammary epithelial cells. Furthermore, 1,25(OH)2D3 increased the intracellular expression of IL1?, which was necessary for the anti-proliferative effects of 1,25(OH)2D3 in mammary cells. Together, these findings support the chemopreventative potential of vitamin D3 in the mammary gland and present a role for IL1? in regulation of mammary cell proliferation by 1,25(OH)2D3.

SUBMITTER: Maund SL

PROVIDER: S-EPMC3820570 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells.

Maund Sophia L SL Shi Lihong L Cramer Scott D SD

PloS one 20131107 11

Breast cancer is the most common non-cutaneous malignancy in American women, and better preventative strategies are needed. Epidemiological and laboratory studies point to vitamin D3 as a promising chemopreventative agent for breast cancer. Vitamin D3 metabolites induce anti-proliferative effects in breast cancer cells in vitro and in vivo, but few studies have investigated their effects in normal mammary epithelial cells. We hypothesized that 1,25(OH)2D3, the metabolically active form of vitami ...[more]

PMID: 24244740

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Project description:BackgroundCalcium is a vital mineral and an indispensable component of milk for ruminants. The regulation of transcellular calcium transport by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3, the active form of vitamin D) has been confirmed in humans and rodents, and regulators, including vitamin D receptor (VDR), calcium binding protein D9k (calbindin-D9k), plasma membrane Ca(2+)-ATPase 1b (PMCA1b), PMAC2b and Orai1, are involved in this process. However, it is still unclear whether 1,25-(OH)2D3 could stimulate calcium transport in the ruminant mammary gland. The present trials were conducted to study the effect of 1,25-(OH)2D3 supplementation and energy availability on the expression of genes and proteins related to calcium secretion in goat mammary epithelial cells.MethodsAn in vitro culture method for goat secreting mammary epithelial cells was successfully established. The cells were treated with different doses of 1,25-(OH)2D3 (0, 0.1, 1.0, 10.0 and 100.0 nmol/L) for calcium transport research, followed by a 3-bromopyruvate (3-BrPA, an inhibitor of glucose metabolism) treatment to determine its dependence on glucose availability. Cell proliferation ratios, glucose consumption and enzyme activities were measured with commercial kits, and real-time quantitative polymerase chain reaction (RT-qPCR), and western blots were used to determine the expression of genes and proteins associated with mammary calcium transport in dairy goats, respectively.Results1,25-(OH)2D3 promoted cell proliferation and the expression of genes involved in calcium transport in a dose-dependent manner when the concentration did not exceed 10.0 nmol/L. In addition, 100.0 nmol/L 1,25-(OH)2D3 inhibited cell proliferation and the expression of associated genes compared with the 10.0 nmol/L treatment. The inhibition of hexokinase 2 (HK2), a rate-limiting enzyme in glucose metabolism, decreased the expression of PMCA1b and PMCA2b at the mRNA and protein levels as well as the transcription of Orai1, indicating that glucose availability was required for goat mammary calcium transport. The optimal concentration of 1,25-(OH)2D3 that facilitated calcium transport in this study was 10.0 nmol/L.ConclusionsSupplementation with 1,25-(OH)2D3 influenced cell proliferation and regulated the expression of calcium transport modulators in a dose- and energy-dependent manner, thereby highlighting the role of 1,25-(OH)2D3 as an efficacious regulatory agent that produces calcium-enriched milk in ruminants when a suitable energy status was guaranteed.

Project description:Previous genomic profiling of immortalized, non-tumorigenic human breast epithelial cells identified a set of 1,25-dihydroxyvitamin D3 (1,25D) regulated genes with potential relevance to breast cancer prevention. In this report, we characterized the effect of 1,25D on a subset of these genes in six cell lines derived from mammary tissue and breast cancers. Non-tumorigenic cell lines included hTERT-HME1, HME and MCF10A cells which are often used to model normal breast epithelial cells. Breast cancer cell lines included MCF7 cells (a model of early stage, estrogen-dependent disease), DCIS.com cells (a derivative of MCF10A cells that models in situ breast cancer) and Hs578T cells (a model of metastatic disease). All of these cell lines express the vitamin D receptor (VDR) and exhibit anti-cancer responses to 1,25D such as changes in proliferation, apoptosis, metabolism, or invasion. Our comparative data demonstrate highly variable responses to 1,25D (100nM, 24h) between the cell lines. In both hTERT-HME1 and HME cell lines, CYP24A1, SLC1A1 and ITGB3 were up-regulated whereas KDR, GLUL and BIRC3 were down-regulated in response to 1,25D. In contrast, no changes in SLC1A1, ITGB3 or GLUL expression were detected in 1,25D treated MCF10A cells although KDR and BIRC3 were down-regulated by 1,25D. The effects of 1,25D on these genes in the breast cancer cell lines were blunted, with the DCIS.com cells exhibiting the most similar responses to the immortalized hTERT-HME1 and HME cells. The differences in cellular responses were not due to general impairment in VDR function as robust CYP24A1 induction was observed in all cell lines. Thus, our data indicate that the genomic changes induced by 1,25D are highly cell-type specific even in model cell lines derived from the same tissue. The implication of these findings is that genomic responses to changes in vitamin D status in vivo are likely to be distinct from individual to individual, particularly in neoplastic tissue. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

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A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells.

Publications

A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells.

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