Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice
Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice
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DOI：
10.1093/carcin/bgh271
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发表时间：
2004-12-01
期刊：
影响因子：
4.7
通讯作者：
Welsh, J
中科院分区：
文献类型：
--
作者：
Zinser, GM;Welsh, J
维生素D-3受体（VDR）是一种配体依赖性转录因子，参与调节乳腺正常细胞和转化细胞的细胞周期、分化和凋亡。在这些研究中，我们检查了VDR状态是否改变了乳腺形态学或在乳腺癌的充分表征的MMTV-neu转基因模型中的转化。我们证明VDR蛋白在肿瘤前病变、已建立的肿瘤和MMTV-neu小鼠肺转移灶的neu阳性上皮细胞中高度表达。此外，缺乏VDR的MMTV-neu小鼠表现出异常的乳腺导管形态学，其特征在于含有发育不良上皮细胞的扩张、膨胀的导管。从12个月大开始，缺乏VDR的MMTV-neu小鼠也会出现体重减轻、乳腺脂肪垫萎缩、雌激素缺乏和存活率降低。缺乏VDR的MMTV-neu小鼠的存活率有限，无法准确评估完全VDR消融对肿瘤发展的影响。然而，VDR杂合子的MMTV-neu小鼠没有表现出体重减轻、乳腺萎缩或存活率降低。与携带两个VDR基因拷贝的MMTV-neu小鼠相比，VDR基因单倍缺陷小鼠的潜伏期缩短，乳腺肿瘤形成率增加。肿瘤组织学和表达/neu转基因的亚细胞定位没有改变VDR单倍不足，尽管在肿瘤VDR表达显着下降。总的来说，这些研究表明，VDR基因剂量的影响与年龄相关的变化，导管形态和癌基因诱导的乳腺肿瘤在体内。
The vitamin D-3 receptor (VDR) is a ligand-dependent transcription factor implicated in regulation of cell cycle, differentiation and apoptosis of both normal and transformed cells derived from mammary gland. In these studies we examined whether VDR status altered mammary gland morphology or transformation in the well-characterized MMTV-neu transgenic model of breast cancer. We demonstrate that VDR protein is highly expressed in neu-positive epithelial cells of preneoplastic lesions, established tumors and lung metastases from MMTV-neu mice. Furthermore, MMTV-neu mice lacking VDR exhibit abnormal mammary ductal morphology characterized by dilated, distended ducts containing dysplastic epithelial cells. From 12 months of age on, MMTV-neu mice lacking VDR also experience body weight loss, atrophy of the mammary fat pad, estrogen deficiency and reduced survival. The limited survival of MMTV-neu mice lacking VDR precluded an accurate assessment of the impact of complete VDR ablation on tumor development. MMTV-neu mice heterozygous for VDR, however, did not exhibit body weight loss, mammary gland atrophy or compromised survival. Compared with MMTV-neu mice with two copies of the VDR gene, haploinsufficiency of VDR shortened the latency and increased the incidence of mammary tumor formation. Tumor histology and expression/subcellular localization of the neu transgene were not altered by VDR haploinsufficiency despite a significant decrease in tumor VDR expression. Collectively, these studies suggest that VDR gene dosage impacts on age-related changes in ductal morphology and oncogene-induced tumorigenesis of the mammary gland in vivo.