CCN1, a candidate target for zoledronic acid treatment in breast cancer.
CCN1, a candidate target for zoledronic acid treatment in breast cancer.
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DOI：
10.1158/1535-7163.mct-10-0836
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发表时间：
2011-05
影响因子：
5.7
通讯作者：
Lupu R
中科院分区：
文献类型：
--
作者：
Espinoza I;Liu H;Busby R;Lupu R
CCN 1，也称为CYR61，是一种在约30%的浸润性乳腺癌中过表达的存活和促血管生成因子，特别是在三阴性乳腺癌（TNBC）中。CCN 1在乳腺癌中的表达促进肿瘤发生、转移、抗激素和化学抗性。TNBC经常发生骨转移，因此绝大多数患者接受双膦酸盐治疗作为化疗的伴随治疗。唑来膦酸（ZOL）是目前使用的一种双膦酸盐，抑制骨吸收，防止肿瘤转移诱导的新溶骨性病变的发展，并且在乳腺癌细胞和肿瘤中具有直接的抗肿瘤活性。我们已经表明，ZOL抑制锚定独立的生长以及分支和形态发生在CCN 1过表达细胞。然而，该机制尚未得到很好的理解。在这项研究中，我们研究了ZOL在乳腺癌细胞中的作用，这些细胞具有高表达水平和不可检测的CCN 1表达水平。我们证明了CCN 1表达细胞对ZOL更敏感，ZOL以剂量依赖性方式诱导CCN 1启动子活性和CCN 1蛋白表达的下调，并且ZOL与磷酸化Akt的减少和CCN 1表达的负调节因子FOXO 3a向细胞核的易位相关。CCN 1启动子中FOXO3a结合位点的缺失防止ZOL抑制CCN 1启动子活性，表明FOXO3a转录激活对于ZOL诱导CCN 1抑制是必需的。该研究提供了ZOL通过FOXO 3a靶向促血管生成因子（CCN 1）的证据，并揭示了ZOL在乳腺癌细胞中作用的新机制。
CCN1, also known as CYR61, is a survival and pro-angiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone and chemo-resistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct anti-tumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and with undetectable CCN1 expression levels. We demonstrate that CCN1 expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity demonstrating that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the pro-angiogenic factor (CCN1) through FOXO3a, and reveals a new mechanism of ZOL action in breast cancer cells.