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1,25-Dihydroxyvitamin D₃ Down-Regulates Estrogen Receptor Abundance and Suppresses Estrogen Actions in MCF-7 Human Breast Cancer Cells¹

Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Because the estrogen receptor (ER) plays a key role in breast cancer progression, we have studied the effects of 1,25(OH)₂D₃ on the regulation of ER in the estrogen-responsive MCF-7 human breast cancer cell line, which is known to predominantly express ER. 1,25(OH)₂D₃ causes significant inhibition of MCF-7 cell growth, and it also decreases the growth-stimulatory effect of 17ß-estradiol (E₂). Treatment of MCF-7 cells with 1,25(OH)₂D₃ reduces ER levels in a dose-dependent manner, as shown by ligand binding assays and Western blot analysis. The 1,25(OH)₂D₃ analogues EB-1089, KH-1060, Ro 27-0574, and Ro 23-7553 are more potent than 1,25(OH)₂D₃ in both their antiproliferative actions as well as ER down-regulation. There is a striking correlation (R² = 0.98) between the growth-inhibitory actions of 1,25(OH)₂D₃ or analogues and their ability to down-regulate ER levels. Treatment with 1,25(OH)₂D₃ shows that the reduction in ER is accompanied by a significant decrease in the steady-state levels of ER mRNA. The decrease in ER mRNA is not abolished by the protein synthesis inhibitor cycloheximide. Inhibition of mRNA synthesis with actinomycin D reveals no significant differences between ER mRNA half-life in control and 1,25(OH)₂D₃-treated cells. Nuclear run-on experiments demonstrate significant decreases in ER gene transcription at the end of 17 h of treatment with 1,25(OH)₂D₃. These findings indicate that 1,25(OH)₂D₃ exerts a direct negative effect on ER gene transcription. Coincident with the decrease in ER levels there is an attenuation of E₂-mediated bioresponses after 1,25(OH)₂D₃ treatment. Induction of progesterone receptor by E₂ is suppressed by 1,25(OH)₂D₃, and the E₂-mediated increase in breast cancer susceptibility gene (BRCA1) protein is reduced by 1,25(OH)₂D₃ treatment. Overall, these results suggest that the antiproliferative effects of 1,25(OH)₂D₃ and its analogues on MCF-7 cells could partially be mediated through their action to down-regulate ER levels and thereby attenuate estrogenic bioresponses, including breast cancer cell growth.

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