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.
ACS Nano. 2017 Jan 24;11(1):335-346. doi: 10.1021/acsnano.6b05910. Epub 2016 Dec 16.
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.
大多数乳腺癌表达雌激素受体（ER）α，抗雌激素药物他莫昔芬已被广泛用于治疗此类癌症。不幸的是，多达一半的 ERα 阳性肿瘤存在内在或获得性内分泌治疗抵抗。我们最近的研究表明，雌激素受体共激活子 Mediator Subunit 1（MED1）通过与 HER2 的串扰在他莫昔芬耐药中发挥关键作用。在此，我们组装了一种三链结（3-WJ）pRNA-HER2apt-siMED1 纳米颗粒，通过 HER2 RNA 适体靶向过表达 HER2 的人乳腺癌，以沉默 MED1 表达。我们发现，这些超紧凑的 RNA 纳米颗粒在 RNase A、血清和 8 M 尿素条件下非常稳定。这些纳米颗粒特异性结合过表达 HER2 的乳腺癌细胞，有效耗尽 MED1 表达，并显著降低 ERα 介导的基因转录，而这些纳米颗粒上 HER2 RNA 适体的点突变则消除了这种功能。这些 RNA 纳米颗粒不仅减少了过表达 HER2 的乳腺癌细胞的生长、转移和类器官形成，而且还使它们对他莫昔芬治疗敏感。这些生物安全纳米颗粒在荷瘤原位移植小鼠模型中系统给药后，不仅能有效地靶向和穿透过表达 HER2 的肿瘤，而且还能大大抑制肿瘤的生长和转移。此外，这些纳米颗粒与他莫昔芬联合治疗体内时，还导致乳腺癌肿瘤中干细胞含量显著减少。总之，我们已经生成了多功能 RNA 纳米颗粒，它们特异性靶向过表达 HER2 的人乳腺癌，沉默 MED1，并克服了他莫昔芬耐药性。
