Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization
Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization
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DOI：
10.1002/jbmr.3744
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发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Seibel, Markus J.
中科院分区：
文献类型：
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作者：
Horas, Konstantin;Zheng, Yu;Seibel, Markus J.
维生素D受体（VDR）的表达被认为与肿瘤进展有关。然而，VDR在乳腺癌骨转移中的作用以及该过程的分子机制尚不清楚。采用全身转移的啮齿动物模型（雌性Balb/c nu/nu小鼠），我们在这里证明了VDR的敲低强烈增加了MDA-MB-231人乳腺癌细胞向骨的转移潜力，导致显著更大的骨骼肿瘤负荷。VDR表达的消融促进癌细胞移动性（迁移）和侵袭性，从而促进骨骼定殖。从机制上讲，肿瘤细胞行为的这些变化归因于参与细胞粘附、增殖和细胞骨架组织的蛋白质表达的变化，这些蛋白质表达是上皮细胞向间充质细胞转化（EMT）的特征模式。与这些实验结果一致，对人乳腺癌标本的分析证实了VDR表达、蛋白表达模式的EMT典型变化和临床预后之间的关联。人乳腺癌细胞中VDR的缺失通过诱导EMT、促进癌细胞的扩散和促进骨中肿瘤集落的形成而标志着肿瘤发生的临界点。(c)2019年美国骨与矿物质研究学会。
Expression of the vitamin D receptor (VDR) is thought to be associated with neoplastic progression. However, the role of the VDR in breast cancer metastasis to bone and the molecular mechanisms underlying this process are unknown. Employing a rodent model (female Balb/c nu/nu mice) of systemic metastasis, we here demonstrate that knockdown of the VDR strongly increases the metastatic potential of MDA-MB-231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden. Ablation of VDR expression promotes cancer cell mobility (migration) and invasiveness, thereby facilitating skeletal colonization. Mechanistically, these changes in tumor cell behavior are attributable to shifts in the expression of proteins involved in cell adhesion, proliferation, and cytoskeletal organization, patterns characteristic for epithelial-to-mesenchymal cell transition (EMT). In keeping with these experimental findings, analyses of human breast cancer specimens corroborated the association between VDR expression, EMT-typical changes in protein expression patterns, and clinical prognosis. Loss of the VDR in human breast cancer cells marks a critical point in oncogenesis by inducing EMT, promoting the dissemination of cancer cells, and facilitating the formation of tumor colonies in bone. (c) 2019 American Society for Bone and Mineral Research.