Banwell Claire M, O'Neill Laura P, Uskokovic Milan R, Campbell Moray J
Department of Medicine, Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):245-9. doi: 10.1016/j.jsbmb.2004.03.081.
Proliferation of the non-malignant breast epithelial cell line, MCF-12A, is sensitively and completely inhibited by 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) (ED90 = 70 nM), We used real time RT-PCR to demonstrate that the relative resistance to 1alpha,25(OH)(2)D(3) of MDA-MB-231 cells (ED50 > 100 nM) correlated with significantly reduced Vitamin D receptor (VDR) and increased NCoR1 nuclear receptor co-repressor mRNA (0.1-fold reduction in VDR and 1.7-fold increase in NCoR1 relative to MCF-12A (P < 0.05)). This molecular lesion can be targeted by co-treating cells with 1alpha,25(OH)(2)D(3) or potent analogs and the histone deacetylation inhibitor trichostatin A (TSA). For example, the co-treatment of 1,25-dihydroxy-16,23,Z-diene-26,27-hexafluoro-19-nor Vitamin D(3) (RO-26-2198) (100 nM) plus TSA results in strong additive antiproliferative effects in MDA-MB-231 cells. This may represent novel chemotherapeutic regime for hormone insensitive breast cancer.
非恶性乳腺上皮细胞系MCF-12A的增殖受到1α,25-二羟基维生素D(3)（1α,25(OH)₂D(3)）的敏感且完全抑制（ED90 = 70 nM）。我们使用实时逆转录聚合酶链反应来证明MDA-MB-231细胞对1α,25(OH)₂D(3)的相对抗性（ED50 > 100 nM）与维生素D受体（VDR）显著降低以及核受体共抑制因子NCoR1 mRNA增加相关（相对于MCF-12A，VDR降低0.1倍，NCoR1增加1.7倍（P < 0.05））。这种分子损伤可以通过用1α,25(OH)₂D(3)或强效类似物与组蛋白去乙酰化抑制剂曲古抑菌素A（TSA）共同处理细胞来靶向。例如，1,25-二羟基-16,23,Z-二烯-26,27-六氟-19-去甲维生素D(3)（RO-26-2198）（100 nM）加TSA的共同处理在MDA-MB-231细胞中产生强烈的相加抗增殖作用。这可能代表了一种针对激素不敏感型乳腺癌的新型化疗方案。
