TWIST1 Expression in Breast Cancer Cells Facilitates Bone Metastasis Formation
TWIST1 Expression in Breast Cancer Cells Facilitates Bone Metastasis Formation
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DOI：
10.1002/jbmr.2215
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发表时间：
2014-08-01
影响因子：
6.2
通讯作者：
Clezardin, Philippe
中科院分区：
文献类型：
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作者：
Croset, Martine;Goehrig, Delphine;Clezardin, Philippe
转录因子TWIST 1诱导上皮-间充质转化和/或逃逸到致癌诱导的故障安全程序，促进乳腺癌细胞在体循环中的内渗及其向肺部的传播。它与乳腺癌骨转移的关系尚不清楚。为了解决这一问题，人趋骨MDA-MB-231/B 02乳腺癌细胞稳定转染Tet-inducible载体编码TWIST 1，其表达特异性抑制在强力霉素（dox）的存在下。在免疫缺陷小鼠中动脉内接种表达TWIST 1的转染子显著增加了这些动物中溶骨性病变的程度，如通过X射线摄影测定的，比携带模拟转染肿瘤的动物大50%。这种差异伴随着骨体积的急剧减少（表明更高的骨破坏）和肿瘤体积的两倍增加相比，携带模拟转染肿瘤的小鼠，如通过组织形态测定。重要的是，在dox存在下抑制MDA-MB-231/B 02细胞中TWIST 1的表达消除了TWIST 1对体内骨转移形成的刺激作用。此外，在肿瘤细胞接种后第7天检查未处理和dox处理动物的骨髓，此时没有放射学溶骨性病变的证据，显示从未处理小鼠骨髓中回收的肿瘤细胞集落数量与dox喂养动物相比显著增加。在体外，TWIST 1的表达促进了肿瘤细胞的侵袭，并增强了microRNA 10 b（miR-10 b）的表达，这是一种促侵袭因子，但对肿瘤细胞的生长不利。在体内，miR-10 b的抑制显著降低了骨髓中表达TWIST 1的乳腺癌细胞的存在。总之，这些结果证实TWIST 1通过依赖于miR-10 b的机制促进乳腺癌骨转移形成，这导致肿瘤负荷增加和骨破坏。(C)2014年美国骨与矿物质研究学会。
The transcription factor TWIST1 induces epithelial-mesenchymal transition and/or escape to the oncogenic-induced failsafe program, facilitating the intravasation of breast cancer cells in the systemic circulation and their dissemination to the lungs. Its involvement in breast cancer bone metastasis is unknown. To address this question, human osteotropic MDA-MB-231/B02 breast cancer cells were stably transfected with a Tet-inducible vector encoding for TWIST1, whose expression was specifically repressed in the presence of doxycycline (dox). The intra-arterial inoculation of transfectants expressing TWIST1 in immunodeficient mice substantially increased the extent of osteolytic lesions in these animals, being 50% larger than that of animals bearing mock-transfected tumors, as determined by radiography. This difference was accompanied by a sharp reduction of the bone volume (indicating a higher bone destruction) and a twofold increase in the tumor volume compared with mice bearing mock-transfected tumors, as determined by histomorphometry. Importantly, the suppression of TWIST1 expression in MDA-MB-231/B02 cells in the presence of dox abolished the stimulatory effect of TWIST1 on bone metastasis formation in vivo. Additionally, examination of the bone marrow from untreated and dox-treated animals on day 7 after tumor cell inoculation, at which time there was no evidence of radiographic osteolytic lesions, revealed that the number of tumor cell colonies that were recovered from the bone marrow of untreated mice was dramatically increased compared with that of dox-fed animals. In vitro, TWIST1 expression promoted tumor cell invasion and enhanced microRNA 10b (miR-10b) expression, a proinvasive factor, but was dispensable for growth of tumor cells. In vivo, the repression of miR-10b substantially decreased the presence of TWIST1-expressing breast cancer cells in the bone marrow. Overall, these results establish that TWIST1 facilitates breast cancer bone metastasis formation through a mechanism dependent of miR-10b, which leads to increase tumor burden and bone destruction. (C) 2014 American Society for Bone and Mineral Research.