title: Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing Using Multifunctional pRNA Nanoparticles.
abstract: Most breast cancers express estrogen receptor (ER) α, and the antiestrogen drug tamoxifen has been widely used for their treatment. Unfortunately, up to half of all ERα-positive tumors have intrinsic or acquired endocrine therapy resistance. Our recent studies revealed that the ER coactivator Mediator Subunit 1 (MED1) plays a critical role in tamoxifen resistance through cross-talk with HER2. Herein, we assembled a three-way junction (3-WJ) pRNA-HER2apt-siMED1 nanoparticle to target HER2-overexpressing human breast cancer via an HER2 RNA aptamer to silence MED1 expression. We found that these ultracompact RNA nanoparticles are very stable under RNase A, serum, and 8 M urea conditions. These nanoparticles specifically bound to HER2-overexpressing breast cancer cells, efficiently depleted MED1 expression, and significantly decreased ERα-mediated gene transcription, whereas point mutations of the HER2 RNA aptamer on these nanoparticles abolished such functions. The RNA nanoparticles not only reduced the growth, metastasis, and mammosphere formation of the HER2-overexpressing breast cancer cells but also sensitized them to tamoxifen treatment. These biosafe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after systemic administration in orthotopic xenograft mouse models. In addition to their ability to greatly inhibit tumor growth and metastasis, these nanoparticles also led to a dramatic reduction in the stem cell content of breast tumors when combined with tamoxifen treatment in vivo. Overall, we have generated multifunctional RNA nanoparticles that specifically targeted HER2-overexpressing human breast cancer, silenced MED1, and overcame tamoxifen resistance.
authors.forename: Yijuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Marissa
authors.initials: M
authors.lastname: Leonard
authors.affiliation: College of Pharmacy, Department of Physiology & Cell Biology, College of Medicine, and Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shu
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Department of Physiology & Cell Biology, College of Medicine, and Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Shu
authors.affiliation: College of Pharmacy, Department of Physiology & Cell Biology, College of Medicine, and Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Peixuan
authors.identifier: 0000-0001-5706-2833
authors.initials: P
authors.lastname: Guo
authors.forename: Xiaoting
authors.identifier: 0000-0002-1328-4255
authors.initials: X
authors.lastname: Zhang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D010582:Bacteriophage lambda / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D012367:RNA, Viral / Q000737:chemistry*; D013499:Surface Properties; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D012367:RNA, Viral; D013629:Tamoxifen
keywords: HER2 RNA aptamer; MED1; breast cancer; pRNA of phi29 DNA packaging motor; tamoxifen resistance