Metastasis of Breast Tumor Cells to Brain Is Suppressed by Phenethyl Isothiocyanate in a Novel In Vivo Metastasis Model

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. The chances of brain metastasis are further elevated in patients with HER2 overexpression. In the current study, we evaluated the anti-metastatic effects of phenethyl isothiocyanate (PEITC) in a novel murine model of breast tumor metastasis. The MDA-MB-231-BR (BR-brain seeking) breast tumor cells stably transfected with luciferase were injected into the left ventricle of mouse heart and the migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent imaging system. In order to study the efficacy of PEITC in preventing the number of tumor cells migrating to brain, mice were given 10 µmol PEITC by oral gavage for ten days prior to intra-cardiac injection of tumor cells labeled with quantum dots. To evaluate the tumor growth suppressive effects, 10 µmol PEITC was given to mice every day starting 14th day after intra-cardiac cell injection. Based on the presence of quantum dots in the brain section of control and treated mice, our results reveal that PEITC significantly prevented the metastasis of breast cancer cells to brain. Our results demonstrate that the growth of metastatic brain tumors in PEITC treated mice was about 50% less than that of control. According to Kaplan Meir’s curve, median survival of tumor bearing mice treated with PEITC was prolonged by 20.5%. Furthermore as compared to controls, we observed reduced HER2, EGFR and VEGF expression in the brain sections of PEITC treated mice. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of PEITC in vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation.乳腺肿瘤转移是全球范围内癌症相关死亡的主要诱因。乳腺肿瘤细胞常发生脑转移，并引发严重的治疗并发症。人表皮生长因子受体2（HER2）过表达的患者，其脑转移风险进一步升高。本研究利用一种新型乳腺肿瘤转移小鼠模型，评估了异硫氰酸苯乙酯（PEITC）的抗转移活性。将稳定转染荧光素酶的MDA-MB-231-BR（BR-脑靶向）乳腺肿瘤细胞接种至小鼠心脏左心室，随后采用无创IVIS生物发光成像系统监测细胞向脑部的迁移情况。为探究PEITC对肿瘤细胞向脑部迁移的抑制效果，研究团队在向小鼠心脏左心室接种量子点标记的肿瘤细胞前10天，通过灌胃方式给予小鼠10 μmol的PEITC。为评估其对肿瘤生长的抑制作用，在细胞心脏左心室接种后的第14天起，每日给予小鼠10 μmol的PEITC。基于对照组与给药组小鼠脑组织切片中量子点的分布情况，本研究结果显示PEITC可显著抑制乳腺癌细胞向脑部的转移。研究结果同时表明，PEITC给药组小鼠的转移性脑肿瘤生长速率较对照组降低约50%。基于凯普兰-迈耶（Kaplan-Meier）曲线分析，PEITC给药组荷瘤小鼠的中位生存期延长了20.5%。与对照组相比，PEITC给药组小鼠脑组织切片中HER2、表皮生长因子受体（EGFR）以及血管内皮生长因子（VEGF）的表达水平均有所降低。据我们所知，本研究首次在新型乳腺肿瘤转移体内模型中证实了PEITC的抗转移活性，为后续临床研究提供了理论依据。