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.

Assessment and comparison of thermal stability of phosphorothioate-DNA, DNA, RNA, 2′-F RNA, and LNA in the context of Phi29 pRNA 3WJ

“…In addition, substituting uridine and cytidine with their 2 ′ -fluoro-modified counterparts further increases nanoparticle stability and prevents digestion by RNases (Layzer et al 2004). 2 ′ -F modified phi29 pRNA 3WJ thus greatly enhances the thermodynamic and enzymatic stability of RNA nanoparticles and has paved the way for medical applications of RNA nanotechnology (Cui et al 2015;Shu et al 2015;Binzel et al 2016b;Zhang et al 2017).…”

Annotation and cluster analysis of long noncoding RNA linked to male sex and estrogen in cancers

“…57 Unfortunately, up to half of ERα-positive tumors have intrinsic or acquired endocrine therapy resistance. 58 Previous studies claimed that E2 inhibits NF-κB-mediated gene transcription, 59,60 and decreased activity of p65 induced by E2 is due to the cytoplasmic sequestration of this transcription factor. 55 Our results showed that LINC00263 is expressed at lower levels in female patients than in male patients.…”

Nucleic Acid–Based Functional Nanomaterials as Advanced Cancer Therapeutics

“…Therefore, the RNA tetrahedrons hold a great potential to serve as a multifunctional nanocarrier for cancer therapy. Zhang and coworkers designed 3WJ‐pRNA‐based nanoparticles for treating breast cancers with tamoxifen resistance (Figure b) . The cross‐talk between coactivator Mediator Subunit 1 (MED1) and HER2 that overexpressed on the cell membrane of human breast cancer cells played a crucial role in the mechanism of tamoxifen resistance .…”

“…b) RNA nanoparticles for gene therapy aimed at drug resistant cancer cells. Adapted with permission . Copyright 2016, American Chemical Society.…”