%0 Journal Article
%T Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down
%A Jos¨¦ L Costa
%A Paul P Eijk
%A Mark A van de Wiel
%A Derk ten Berge
%A Fernando Schmitt
%A Carmen J Narvaez
%A JoEllen Welsh
%A Bauke Ylstra
%J BMC Genomics
%D 2009
%I BioMed Central
%R 10.1186/1471-2164-10-499
%X 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.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.Strong anti-proliferative effects of 1,25-dihydroxyvitamin D3 (1,25D) have been demonstrated in a wide spectrum of solid cancers, in vitro and in animal models [1]. A link between 1,25D status and cancer has also been demonstrated in epidemiological studies. Together these data lead to a number of clinical trials to test the efficacy of 1,25D or synthetic analogs [2]. Yet, the molecular mechanisms by which the 1,25D pathway exerts its anti-proliferative effects remain unclear. There is much need for detailed knowledge of the molecular mechanism behind the anti-proliferative action of 1,25D, since calcemic side-effects form a major obstacle for the development of 1,25D or derivative drugs. Classically, 1,25D mediates the maintenance of calcium homeostasis through activation of the vitamin D receptor (VDR), a ligand depen
%U http://www.biomedcentral.com/1471-2164/10/499