Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down
1 Department of Pathology, VU University Medical Center (VUMC), Amsterdam, The Netherlands
2 Institute of Molecular Pathology and Immunology of the University of Porto - IPATIMUP, University of Porto, Portugal
3 Department of Epidemiology and Biostatistics, VU University Medical Center (VUMC), Amsterdam, The Netherlands
4 Erasmus Stem Cell Institute, Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands
5 Medical Faculty of Porto University, Porto, Portugal
6 GenNYsis Center for Excellence in Cancer Genomics, and Department of Biomedical Sciences, University at Albany, New York, USA
7 Department of Mathematics, VU University, Amsterdam
BMC Genomics 2009, 10:499 doi:10.1186/1471-2164-10-499Published: 28 October 2009
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).
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.