Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.
Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.
复制标题
乳腺癌细胞通过 BMP2/RUNX2 信号通路诱导的上皮间质转化获得仿骨特征
DOI：
10.18632/oncotarget.12939
复制
发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Feng YM
中科院分区：
文献类型：
--
作者：
Tan CC;Li GX;Tan LD;Du X;Li XQ;He R;Wang QS;Feng YM
骨是乳腺癌转移最常见的器官之一。通过表达骨基质蛋白和因子来模拟成骨细胞的癌细胞具有更高的转移到骨的可能性。然而，癌细胞的拟骨形成的分子机制仍然不确定。在此，我们确定了一组骨相关基因（BRG），异位共表达的原发性乳腺癌组织，并确定拟骨功能是由于上皮乳腺癌细胞，经历了上皮间质转化（EMT），然后骨形态发生蛋白-2（BMP-2）刺激的成骨细胞样转化。此外，我们证明，乳腺癌细胞转化成成骨样细胞与BRG的高表达表现出增强的趋化性，粘附，增殖和多药耐药在成骨细胞模拟骨微环境在体外。在这些过程中，runt-related transcription factor 2（RUNX 2）通过抑制或激活乳腺癌细胞中TGF-β/SMAD和BMP/SMAD信号通路之间的动态拮抗作用的基础BRG的转录，作为主介质发挥作用。我们的研究结果表明，在原发性乳腺肿瘤中出现了一种新的拟骨形成机制，这可能解释了乳腺癌转移到骨骼的倾向，并有助于预测和靶向乳腺癌骨转移和多药耐药的潜在策略。
Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-β/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance.