Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.
Breast Cancer Res Treat. 2012 Nov;136(1):89-105. doi: 10.1007/s10549-012-2238-7. Epub 2012 Sep 15.
Breast cancer is one of the most common cancers in women worldwide and metastasis is the major cause of breast cancer death. Development of new therapeutic agents for inhibiting breast cancer metastasis is therefore an urgent need. We previously demonstrated that recombinant DNA-derived viral capsid protein VP1 (rVP1) of foot-and-mouth disease virus-induced apoptosis of MCF-7 breast cancer cells in vitro. Here, we investigated whether rVP1 exhibits any inhibitory effects on migration/metastasis and human epidermal growth factor receptor 2 (HER-2), a well-known biomarker for poor prognosis of breast cancer. The effects of rVP1 on cancer cell migration/invasion and metastasis were evaluated using Transwell migration assay and animal cancer models of metastasis. Western blotting, RT-PCR, flow cytometry, immunohistochemistry, and immunofluorescence staining techniques were used to investigate the effects of rVP1 on HER-2 and signal transduction mediators. Non-cytotoxic concentrations of rVP1-induced mesenchymal-epithelial transition and significantly suppressed AP-2α and HER-2 expression as well as the migration and invasion of a variety of breast cancer cell lines in a β1-integrin-dependent manner in vitro. Gross and histopathologic examinations showed that rVP1 also suppressed metastasis of several breast cancer cell lines, including HER-2-overexpressing SK-BR-3 and BT-474 cells to lung, liver, or peripheral lymph node in orthotopic allograft/xenograft murine models. In addition, rVP1 significantly prolonged survival in breast cancer-bearing mice. Notably, no apparent side effects of rVP1 were detected, as shown by normal complete blood count levels and serum biochemistry profiles, including AST, ALT, BUN, and creatine. This study demonstrates that rVP1 suppresses the migration, invasion, and metastasis of breast cancer cells via binding to β1 integrin receptor and down-regulation of AP-2α and HER-2 expression. The effectiveness of rVP1 on inhibiting migration/metastasis of breast cancer and HER-2 expression suggests that it may be suitable for serving as potential therapeutics for metastatic breast cancer particularly HER-2-overexpressing cancer.
乳腺癌是全世界女性最常见的癌症之一，转移是乳腺癌死亡的主要原因。因此，开发抑制乳腺癌转移的新治疗剂是当务之急。我们之前证明，口蹄疫病毒的重组 DNA 衍生的病毒衣壳蛋白 VP1(rVP1)在体外诱导 MCF-7 乳腺癌细胞凋亡。在这里，我们研究了 rVP1 是否对迁移/转移和人表皮生长因子受体 2(HER-2)有任何抑制作用，HER-2 是乳腺癌预后不良的一个众所周知的生物标志物。使用 Transwell 迁移测定和动物转移癌症模型评估 rVP1 对癌细胞迁移/侵袭和转移的影响。使用 Western blot、RT-PCR、流式细胞术、免疫组织化学和免疫荧光染色技术研究 rVP1 对 HER-2 和信号转导介质的影响。非细胞毒性浓度的 rVP1 诱导间质上皮转化，并显著抑制 AP-2α 和 HER-2 表达，以及各种乳腺癌细胞系在体外以β1 整合素依赖性方式迁移和侵袭。大体和组织病理学检查表明，rVP1 还抑制了几种乳腺癌细胞系的转移，包括 HER-2 过表达的 SK-BR-3 和 BT-474 细胞到肺、肝或外周淋巴结的原位同种异体/异种移植小鼠模型。此外，rVP1 显著延长了荷瘤小鼠的存活时间。值得注意的是，rVP1 没有明显的副作用，如正常的全血细胞计数水平和血清生化谱，包括 AST、ALT、BUN 和肌酸。这项研究表明，rVP1 通过与β1 整合素受体结合并下调 AP-2α 和 HER-2 表达来抑制乳腺癌细胞的迁移、侵袭和转移。rVP1 抑制乳腺癌迁移/转移和 HER-2 表达的有效性表明，它可能适合作为转移性乳腺癌特别是 HER-2 过表达癌症的潜在治疗剂。
