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Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Transcriptional effects of 1,25 dihydroxyvitamin D3physiological and supra-physiological concentrations in breast cancer organotypic culture

Authors: Cintia Milani, Maria Lucia Hirata Katayama, Eduardo Carneiro de Lyra, JoEllen Welsh, Laura Tojeiro Campos, M Mitzi Brentani, Maria do Socorro Maciel, Rosimeire Aparecida Roela, Paulo Roberto del Valle, João Carlos Guedes Sampaio Góes, Suely Nonogaki, Rodrigo Esaki Tamura, Maria Aparecida Azevedo Koike Folgueira

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Vitamin D transcriptional effects were linked to tumor growth control, however, the hormone targets were determined in cell cultures exposed to supra physiological concentrations of 1,25(OH)2D3 (50-100nM). Our aim was to evaluate the transcriptional effects of 1,25(OH)2D3 in a more physiological model of breast cancer, consisting of fresh tumor slices exposed to 1,25(OH)2D3 at concentrations that can be attained in vivo.

Methods

Tumor samples from post-menopausal breast cancer patients were sliced and cultured for 24 hours with or without 1,25(OH)2D3 0.5nM or 100nM. Gene expression was analyzed by microarray (SAM paired analysis, FDR≤0.1) or RT-qPCR (p≤0.05, Friedman/Wilcoxon test). Expression of candidate genes was then evaluated in mammary epithelial/breast cancer lineages and cancer associated fibroblasts (CAFs), exposed or not to 1,25(OH)2D3 0.5nM, using RT-qPCR, western blot or immunocytochemistry.

Results

1,25(OH)2D3 0.5nM or 100nM effects were evaluated in five tumor samples by microarray and seven and 136 genes, respectively, were up-regulated. There was an enrichment of genes containing transcription factor binding sites for the vitamin D receptor (VDR) in samples exposed to 1,25(OH)2D3 near physiological concentration. Genes up-modulated by both 1,25(OH)2D3 concentrations were CYP24A1, DPP4, CA2, EFTUD1, TKTL1, KCNK3. Expression of candidate genes was subsequently evaluated in another 16 samples by RT-qPCR and up-regulation of CYP24A1, DPP4 and CA2 by 1,25(OH)2D3 was confirmed. To evaluate whether the transcripitonal targets of 1,25(OH)2D3 0.5nM were restricted to the epithelial or stromal compartments, gene expression was examined in HB4A, C5.4, SKBR3, MDA-MB231, MCF-7 lineages and CAFs, using RT-qPCR. In epithelial cells, there was a clear induction of CYP24A1, CA2, CD14 and IL1RL1. In fibroblasts, in addition to CYP24A1 induction, there was a trend towards up-regulation of CA2, IL1RL1, and DPP4. A higher protein expression of CD14 in epithelial cells and CA2 and DPP4 in CAFs exposed to 1,25(OH)2D3 0.5nM was detected.

Conclusions

In breast cancer specimens a short period of 1,25(OH)2D3 exposure at near physiological concentration modestly activates the hormone transcriptional pathway. Induction of CYP24A1, CA2, DPP4, IL1RL1 expression appears to reflect 1,25(OH)2D3 effects in epithelial as well as stromal cells, however, induction of CD14 expression is likely restricted to the epithelial compartment.
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Metadata
Title
Transcriptional effects of 1,25 dihydroxyvitamin D3physiological and supra-physiological concentrations in breast cancer organotypic culture
Authors
Cintia Milani
Maria Lucia Hirata Katayama
Eduardo Carneiro de Lyra
JoEllen Welsh
Laura Tojeiro Campos
M Mitzi Brentani
Maria do Socorro Maciel
Rosimeire Aparecida Roela
Paulo Roberto del Valle
João Carlos Guedes Sampaio Góes
Suely Nonogaki
Rodrigo Esaki Tamura
Maria Aparecida Azevedo Koike Folgueira
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-119

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