title: RNA-based TWIST1 inhibition via dendrimer complex to reduce breast cancer cell metastasis.
abstract: 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.
authors.affiliation: 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.
authors.forename: James
authors.initials: J
authors.lastname: Finlay
authors.affiliation: 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.
authors.forename: Cai M
authors.initials: CM
authors.lastname: Roberts
authors.affiliation: Department of Neurosciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Lowe
authors.affiliation: Department of Biological Sciences, California State University, Los Angeles, 5151 State University Drive, Los Angeles, CA 90032-8201, USA.
authors.forename: Joana
authors.initials: J
authors.lastname: Loeza
authors.affiliation: Irell & Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.affiliation: Department of Neurosciences, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Carlotta A
authors.initials: CA
authors.lastname: Glackin
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D050091:Dendrimers / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012313:RNA / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection / Q000379:methods; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D050091:Dendrimers; D009687:Nuclear Proteins; C104700:PAMAM Starburst; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D012313:RNA