SREBP-2 aggravates breast cancer associated osteolysis by promoting osteoclastogenesis and breast cancer metastasis
SREBP-2 aggravates breast cancer associated osteolysis by promoting osteoclastogenesis and breast cancer metastasis
复制标题
SREBP-2通过促进破骨细胞生成和乳腺癌转移加重乳腺癌相关的骨溶解
DOI：
10.1016/j.bbadis.2018.10.026
复制
发表时间：
2019-01-01
影响因子：
6.2
通讯作者：
Fan, Shunwu
中科院分区：
文献类型：
--
作者：
Jie, Zhiwei;Xie, Ziang;Fan, Shunwu
骨骼是乳腺癌最常见的转移部位之一，也是这些患者高死亡率的主要原因。因此，进一步了解调控乳腺癌诱导的骨溶解的分子机制对于开发更有效的治疗方法至关重要。在这项研究中，我们证明了类固醇调节元件结合蛋白2(SREBP-2)在破骨细胞的形成和功能以及乳腺癌转移中起重要作用。研究发现，在RANKL/cAMP反应元件结合蛋白(CREB)信号通路的调控下，SREBP-2在破骨细胞形成的早期阶段被诱导表达。SREBP-2随后被转移到细胞核中，在那里它与其他转录因子一起诱导成熟破骨细胞形成所需的NFATCL的表达。此外，还发现SREBP-2在乳腺癌组织中高表达，并与预后不良相关。SREBP-2同样受CREB的转录调控，它的诱导调节基质金属蛋白酶(MMPs)的表达，MMPs是参与乳腺癌细胞骨转移的关键降解酶。因此，靶向SREBP-2的Fatostatin可以特异性地抑制SREBP裂解激活蛋白(SCAP)并阻止SREBP的激活，从而在体内减轻乳腺癌诱导的骨溶解。综上所述，我们的结果表明SREBP-2在调节破骨细胞生成中起关键作用，并有助于乳腺癌诱导的骨溶解。因此，抑制SREBP-2是乳腺癌患者骨溶解病变的一种潜在的治疗方法。
Bone is one of the most common sites of breast cancer metastasis and a major cause of high mortality in these patients. Thus, further understanding the molecular mechanisms regulating breast cancer-induced osteolysis is critical for the development of more effective treatments. In this study, we demonstrated that important roles sterol regulatory element-binding protein 2 (SREBP-2) play in osteoclast formation a function, and in breast cancer metastasis. SREBP-2 expression was found to be induced during the early stages of osteoclast formation under the control of the RANKL/cAMP-response element binding protein (CREB) signaling cascade. SREBP-2 is subsequently translocated into the nucleus where it participates with other transcriptional factors to induce the expression of NFATcl required for mature osteoclast formation. Additionally, SREBP-2 was also found to be highly expressed in breast cancer tissues and correlated with a poor prognosis. SREBP-2 was similarly under the transcriptional control of CREB and its induction regulates the expression of matrix metalloproteinases (MMPs), key degradative enzymes involved in bone metastases by breast cancer cells. Accordingly, targeting of SREBP-2 with Fatostatin which specifically inhibits SCAP (SREBP cleavage-activating protein) and prevents SREBP activation, attenuated breast cancer-induced osteolysis in vivo. Collectively, our results suggest that SREBP-2 plays a critical role in regulating osteoclastogenesis and contributes to breast cancer-induced osteolysis. Thus, SREBP-2 inhibition is a potential therapeutic approach for breast cancer patients with osteolytic bone lesions.