Department of Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55905, USA.
Mol Cancer Ther. 2011 May;10(5):732-41. doi: 10.1158/1535-7163.MCT-10-0836. Epub 2011 Mar 10.
CCN1, also known as CYR61, is a survival and proangiogenic 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 chemoresistance. 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 antitumor 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 undetectable CCN1 expression levels. We show 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 showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells.
CCN1，也称为 CYR61，是大约 30%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。乳腺癌中 CCN1 的表达促进肿瘤发生、转移、抗激素和化疗耐药性。TNBC 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辅助治疗。唑来膦酸（ZOL）是目前使用的一种双膦酸盐，可抑制骨吸收，防止肿瘤转移引起的新溶骨性病变的发展，并且对乳腺癌细胞和肿瘤具有直接的抗肿瘤活性。我们已经表明，ZOL 抑制锚定非依赖性生长以及 CCN1 过表达细胞中的分支和形态发生。然而，其机制尚不清楚。在这项研究中，我们研究了 ZOL 对高表达和未检测到 CCN1 表达水平的乳腺癌细胞的影响。我们表明，CCN1 表达细胞对 ZOL 更为敏感，ZOL 以剂量依赖性方式诱导 CCN1 启动子活性和 CCN1 蛋白表达下调，并且 ZOL 与磷酸化 Akt 的减少和 FOXO3a 的易位相关，后者是 CCN1 表达的负调节因子，进入细胞核。CCN1 启动子中 FOXO3a 结合位点的缺失可防止 ZOL 抑制 CCN1 启动子活性，表明 FOXO3a 转录激活是 ZOL 诱导 CCN1 抑制所必需的。这项研究提供了证据表明 ZOL 通过 FOXO3a 靶向促血管生成因子（CCN1），并揭示了 ZOL 在乳腺癌细胞中的新作用机制。
