Sensitivity to growth suppression by 1alpha,25-dihydroxyvitamin D(3) among MCF-7 clones correlates with Vitamin D receptor protein induction.
The antiproliferative effect of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) has been studied for a decade in diverse model systems, but the signalling pathways linking 1alpha,25(OH)(2)D(3) to cell cycle arrest remains unclear. In our attempt to establish a model system which would allow further identification of important players in the process of the 1alpha,25(OH)(2)D(3) imposed cell cycle arrest, we have isolated derivatives of the human breast cancer cell line MCF-7 and chosen two nearly 1alpha,25(OH)(2)D(3) resistant and two hypersensitive sub-clones. Investigation of cell cycle proteins regulated by 1alpha,25(OH)(2)D(3) in these clones indicates that activation of one component/pathway is responsible for the linkage between 1alpha,25(OH)(2)D(3) and growth arrest. Protein levels of the Vitamin D receptor (VDR) were elevated in sensitive cells upon 1alpha,25(OH)(2)D(3) treatment, whereas resistant clones were unable to induce VDR upon 1alpha,25(OH)(2)D(3) treatment. Our data show that VDR protein levels and the ability of a cell to induce VDR upon 1alpha,25(OH)(2)D(3) treatment correlate with the antiproliferative effects of 1alpha,25(OH)(2)D(3), and suggest that the level of VDR in cancer cells might serve as a prognostic marker for treatment of cancer with 1alpha,25(OH)(2)D(3) analogues.
Department of Biochemistry, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark. simon@kemi.dtu.dk
Simon Skjøde
SS
Jensen
Mogens Winkel
MW
Madsen
Jiri
J
Lukas
Jiri
J
Bartek
Lise
L
Binderup
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002999:Clone Cells; D017931:DNA Primers; D006801:Humans; D008024:Ligands; D018167:Receptors, Calcitriol / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D017931:DNA Primers; D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol