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Logo of bmcgenoBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Genomics
 
BMC Genomics. 2009; 10: 499.
Published online Oct 28, 2009. doi:  10.1186/1471-2164-10-499
PMCID: PMC2778664
Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down
José L Costa,corresponding author1,2 Paul P Eijk,1 Mark A van de Wiel,3,7 Derk ten Berge,4 Fernando Schmitt,2,5 Carmen J Narvaez,6 JoEllen Welsh,6 and Bauke Ylstra1
1Department of Pathology, VU University Medical Center (VUMC), Amsterdam, The Netherlands
2Institute of Molecular Pathology and Immunology of the University of Porto - IPATIMUP, University of Porto, Portugal
3Department of Epidemiology and Biostatistics, VU University Medical Center (VUMC), Amsterdam, The Netherlands
4Erasmus Stem Cell Institute, Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
5Medical Faculty of Porto University, Porto, Portugal
6GenNYsis Center for Excellence in Cancer Genomics, and Department of Biomedical Sciences, University at Albany, New York, USA
7Department of Mathematics, VU University, Amsterdam
corresponding authorCorresponding author.
José L Costa: jcosta/at/ipatimup.pt; Paul P Eijk: pp.eijk/at/vumc.nl; Mark A van de Wiel: mark.vdwiel/at/vumc.nl; Derk ten Berge: d.tenberge/at/erasmucmc.nl; Fernando Schmitt: fschmitt/at/ipatimup.pt; Carmen J Narvaez: narvaez.2/at/nd.edu; JoEllen Welsh: jwelsh/at/uamail.albany.edu; Bauke Ylstra: b.ylstra/at/vumc.nl
Received June 17, 2009; Accepted October 28, 2009.
Abstract
Background
The active form of Vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), has strong anti-proliferative effects, yet the molecular mechanisms underneath this effect remain unclear. In contrast, the molecular mechanism of 1,25D for the regulation of calcium homeostasis has principally been resolved, demonstrating a pivotal role for the vitamin D receptor (VDR).
Results
We first addressed the question whether the anti-proliferative effects of 1,25D are influenced by VDR. Knockdown of VDR by siRNA did not affect the anti-proliferative effects of 1,25D in MCF7 breast cancer cells. This unanticipated finding led us to take an alternative approach using genome wide screens to study the molecular mechanisms of 1,25D in proliferation. For that purpose, four independently developed and stable 1,25D resistant MCF7 cell lines were analyzed. Array CGH identified a copy number alteration in a region of 13.5 Mb at chromosome 11q13.4-14.1 common to all four 1,25D resistant cell lines. Expression arrays revealed that no single gene was differentially expressed between the sensitive and resistant cells, but multiple membrane receptor signaling pathways were altered in the 1,25D resistant cell lines. Importantly, in the genome wide experiments neither VDR, CYP24A1 nor other known vitamin D signaling pathway genes were associated with 1,25D resistance.
Conclusion
In conclusion, siRNA and genome wide studies both suggest that the anti-proliferative effects of 1,25D in MCF7 breast tumor cell lines do not rely on classical Vitamin D pathway per se.
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