Nolan E, Donepudi M, VanWeelden K, Flanagan L, Welsh J
W. Alton Jones Cell Science Center, Lake Placid, New York 12946, USA.
Mol Cell Biochem. 1998 Nov;188(1-2):13-20.
Our studies have identified 1,25(OH)2D3 as a coordinate regulator of proliferation and apoptosis in breast cancer cells. In MCF-7 cells, 1,25(OH)2D3 down regulates the estrogen receptor (ER), suggesting that the effects of 1,25(OH)2D3 may be linked to disruption of estrogen regulated survival signals. Although studies have demonstrated that 1,25(OH)2D3 inhibits growth of ER negative breast cancer cells, previous data were generated by comparison of cell lines derived from heterogeneous human tumors and harboring diverse genetic alterations. To provide more conclusive evidence for independent growth regulatory pathways mediated by antiestrogens and 1,25(OH)2D3, we examined vitamin D3 sensitivity in MCf-7 cells selected for resistance to ICI 182, 780 (Zeneca, Macclesfield, UK). The clones we selected for resistance to ICI 182,780 retain functional VDR and undergo 1,25(OH)2D3 mediated growth arrest and apoptosis, in vitro and in vivo, despite loss of estrogen dependence. Cell cycle data indicate that treatment of parental or anti-estrogen resistant MCF-7 clones with 1,25(OH)2D3, in the presence or absence of ICI 182,780, increases the percentage of cells in G0/G1 while reducing the number of cells in S phase. In addition, 1,25(OH)2D3 induces characteristic features of apoptosis, including DNA fragmentation, in both parental and anti-estrogen resistant MCF-7 cells. Furthermore, we report that cells selected for vitamin D3 resistance retain sensitivity to ICI 182,780 mediated growth arrest and apoptosis. This work emphasizes that vitamin D3 compounds and anti-estrogens trigger growth arrest and apoptosis in breast cancer cells by distinct mechanisms, and that breast cancer cell sensitivity to 1,25(OH)2D3 is not diminished during the progression to estrogen independence.
我们的研究已确定1,25(OH)₂D₃是乳腺癌细胞增殖和凋亡的协同调节因子。在MCF-7细胞中，1,25(OH)₂D₃下调雌激素受体（ER），这表明1,25(OH)₂D₃的作用可能与雌激素调节的生存信号中断有关。尽管研究表明1,25(OH)₂D₃可抑制ER阴性乳腺癌细胞的生长，但之前的数据是通过比较源自异质性人类肿瘤且具有多种基因改变的细胞系得出的。为了为抗雌激素和1,25(OH)₂D₃介导的独立生长调节途径提供更确凿的证据，我们检测了对ICI 182,780（英国麦克尔斯菲尔德的阿斯利康公司）耐药的MCF-7细胞对维生素D₃的敏感性。我们选择的对ICI 182,780耐药的克隆保留了功能性维生素D受体（VDR），并且在体外和体内均经历1,25(OH)₂D₃介导的生长停滞和凋亡，尽管失去了雌激素依赖性。细胞周期数据表明，在有或没有ICI 182,780的情况下，用1,25(OH)₂D₃处理亲本或抗雌激素耐药的MCF-7克隆，会增加G₀/G₁期细胞的百分比，同时减少S期细胞的数量。此外，1,25(OH)₂D₃在亲本和抗雌激素耐药的MCF-7细胞中均诱导凋亡的特征性表现，包括DNA片段化。此外，我们报告称，选择对维生素D₃耐药的细胞对ICI 182,780介导的生长停滞和凋亡仍保持敏感性。这项工作强调，维生素D₃化合物和抗雌激素通过不同机制触发乳腺癌细胞的生长停滞和凋亡，并且在向雌激素非依赖性进展过程中，乳腺癌细胞对1,25(OH)₂D₃的敏感性并未降低。
