Finlay James, Roberts Cai M, Lowe Gina, Loeza Joana, Rossi John J, Glackin Carlotta A
Department of Neurosciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA ; Division of Comparative Medicine, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.
Department of Neurosciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.
Biomed Res Int. 2015;2015:382745. doi: 10.1155/2015/382745. Epub 2015 Feb 11.
Breast cancer is the leading cause of cancer-related deaths among women in the United States, and survival rates are lower for patients with metastases and/or triple-negative breast cancer (TNBC; ER, PR, and Her2 negative). Understanding the mechanisms of cancer metastasis is therefore crucial to identify new therapeutic targets and develop novel treatments to improve patient outcomes. A potential target is the TWIST1 transcription factor, which is often overexpressed in aggressive breast cancers and is a master regulator of cellular migration through epithelial-mesenchymal transition (EMT). Here, we demonstrate an siRNA-based TWIST1 silencing approach with delivery using a modified poly(amidoamine) (PAMAM) dendrimer. Our results demonstrate that SUM1315 TNBC cells efficiently take up PAMAM-siRNA complexes, leading to significant knockdown of TWIST1 and EMT-related target genes. Knockdown lasts up to one week after transfection and leads to a reduction in migration and invasion, as determined by wound healing and transwell assays. Furthermore, we demonstrate that PAMAM dendrimers can deliver siRNA to xenograft orthotopic tumors and siRNA remains in the tumor for at least four hours after treatment. These results suggest that further development of dendrimer-based delivery of siRNA for TWIST1 silencing may lead to a valuable adjunctive therapy for patients with TNBC.
乳腺癌是美国女性癌症相关死亡的主要原因，对于发生转移和/或三阴性乳腺癌（TNBC；雌激素受体、孕激素受体和人表皮生长因子受体2均为阴性）的患者，其生存率较低。因此，了解癌症转移机制对于确定新的治疗靶点和开发新的治疗方法以改善患者预后至关重要。一个潜在的靶点是TWIST1转录因子，它在侵袭性乳腺癌中常过度表达，并且是通过上皮-间质转化（EMT）调控细胞迁移的主要调节因子。在此，我们展示了一种基于小干扰RNA（siRNA）的TWIST1沉默方法，该方法通过使用修饰的聚（酰胺胺）（PAMAM）树枝状大分子进行递送。我们的结果表明，SUM1315三阴性乳腺癌细胞能有效摄取PAMAM-siRNA复合物，导致TWIST1及EMT相关靶基因的显著敲低。转染后敲低效果可持续长达一周，并导致迁移和侵袭能力降低，这通过伤口愈合试验和Transwell试验得以确定。此外，我们证明PAMAM树枝状大分子可以将siRNA递送至异种移植原位肿瘤，并且治疗后siRNA在肿瘤中至少保留4小时。这些结果表明，进一步开发基于树枝状大分子递送siRNA以沉默TWIST1的方法可能会为三阴性乳腺癌患者带来有价值的辅助治疗。
