Local microRNA delivery targets Palladin and prevents metastatic breast cancer

Abstract

Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3′-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…Many of the same authors were also involved in another study involving local miR-96 or miR-182 treatment for targeting Palladin, a gene involved in the invasive behavior of breast cancer cells, thereby preventing metastatic breast cancer. [172] An oxidized AuNP-dextran-dendrimer based hydrogel system was used to provide an effective local, selective, and sustained release of miR-96/miR-182, and demonstrated prominent suppression of metastasis in a mouse breast cancer model. By combining the codelivery of miRNAs with the chemotherapy drug, cisplatin, significant primary tumor reduction and metastasis inhibition were obtained.…”

An analysis on Cancer Nanotherapy: does Nanotechnology have a delivery problem?

“…This study introduces the therapeutic potential of miRNAs in breast cancer metastasis prevention. This novel combined therapy can definitely improve the clinical outcome by significantly reducing primary tumor mass, as well as reducing -or even preventingmetastasis [30].…”

“…However, Gilam et al reported the development of a local hydrogel platform applied in a primary breast tumor, which is able to prevent the establishment of metastasis in the lungs, liver and brain [30], just by targeting and modulating the primary tumor microenvironment. In this study the authors developed a smart delivery vehicle based on hydrogel-embedded gold-nanoparticles providing efficient local and selective sustained release of miR-96 and miR-182, as well as combined therapy of miRNAs with a chemotherapy drug, which dramatically suppressed metastasis in an in vivo orthotopic breast cancer mouse model.…”

Self-Healing Hydrogels as Biomedical Scaffolds for Cell, Gene and Drug Delivery

“…RNA-based therapeutics, such as small-interfering (siRNAs), microRNAs (miRNAs), antisense oligonucleotides (ASOs), aptamers, synthetic mRNAs and CRISPR-Cas9, there is great potential to attack genes and genetic products that are currently untreatable, and to produce a new treatment model in the disease [82][83][84] . Since the first RNA interference report (RNAi) in 1998, there has been great interest in applying RNAi therapy to inhibit histopathological gene expression.…”