Functions of 1α,25-dihydroxyvitamin D3 in mammary gland:: from normal development to breast cancer
Functions of 1α,25-dihydroxyvitamin D3 in mammary gland:: from normal development to breast cancer
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DOI：
10.1016/s0039-128x(00)00202-6
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发表时间：
2001-03-01
期刊：
影响因子：
2.7
通讯作者：
Welsh, J
中科院分区：
文献类型：
--
作者：
Narvaez, CJ;Zinser, G;Welsh, J
本文综述了1α，25(OH)(2)D-3(1，25D)和维生素D-3受体在正常和转化的乳腺上皮细胞生长调节中的作用。1，25D在MCF-7等转化的乳腺细胞中既有抗增殖作用，又有促凋亡作用。1，25D的抗增殖作用与抑制生长刺激信号和增强生长抑制信号有关，这些信号导致细胞周期调节因子如p21、p27、细胞周期蛋白和Rb的改变。1，25D的促凋亡作用涉及调节线粒体完整性的bcl2家族成员的相对比例的改变。在MCF-7人乳腺癌细胞中，1，25D介导的细胞凋亡与促凋亡蛋白Bax移位到线粒体，产生活性氧物种，线粒体膜电位的消散和细胞色素c的释放有关。这些线粒体事件以caspase不依赖的方式触发细胞凋亡，因为caspase抑制剂不能拯救1，25D处理的细胞。在VDR缺失的小鼠中，1，25D在正常乳腺上皮细胞的生长和分化中的潜在作用已经被研究。初步数据显示，与年龄匹配的野生型小鼠相比，VDR缺失小鼠的导管分化显著减少，反映为VDR缺失小鼠未分化的末端芽数量增加。这些数据表明，1，25D促进了乳腺发育早期的分化。综上所述，我们的研究表明，维生素D-3内分泌系统在控制乳腺上皮细胞的增殖、分化和凋亡方面发挥着越来越大的作用。(C)2001 Elsevier Science Inc.保留所有权利。
This review examines the role of 1 alpha ,25(OH)(2)D-3 (1,25D) and the vitamin D-3 receptor in growth regulation of normal and transformed mammary epithelial cells. 1,25D exerts both anti-proliferative and pro-apoptotic functions in transformed mammary cells such as MCF-7. The anti-proliferative effects of 1,25D have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21, p27, cyclins and Rb. The pro-apoptotic effects of 1,25D involve alterations in the relative ratios of the bcl-2 family members which regulate mitochondrial integrity. In MCF-7 human breast cancer cells, 1,25D mediated apoptosis is associated with translocation of the pro-apoptotic protein Bax to the mitochondria, generation of reactive oxygen species, dissipation of the mitochondrial membrane potential and release of cytochrome c. These mitochondrial events trigger apoptosis in a caspase-independent manner, since caspase inhibitors do not rescue 1,25D treated cells from death. The potential role of 1,25D in growth and differentiation of normal mammary epithelial cells has been examined in VDR null mice. Initial data indicates a significant decrease in ductal differentiation in VDR null mice compared to age matched wild type mice, reflected as an increased number of undifferentiated terminal end buds in the VDR null mouse. These data suggest that 1,25D promotes differentiation during early mammary gland development. In summary, our studies suggest an expanding role for the vitamin D-3 endocrine system in control of proliferation, differentiation and apoptosis of mammary epithelial cells. (C) 2001 Elsevier Science Inc. All rights reserved.