Abstract 52P
Background
Triple-negative breast cancer (TNBC) represents 20% of breast cancer (BC) patients. There are no common molecular targets and no effective targeted therapies for TNBC. microRNAs (miRNAs) are 18-20 nt long non-coding RNAs and are often dysregulated in cancer cells. Tumor-suppressive miRNAs specifically silence their protooncogenic target genes (mRNAs) by binding specifically to their 3’-UTRs located in their target mRNAs, leading to inhibition of oncogenes that play critical roles in cell proliferation, cell cycle, migration, invasion, angiogenesis, drug resistance, tumor growth, and progression.
Methods
We demonstrated that Eukaryotic Elongation factor-2 kinase (eEF2K) and AXL are oncogenic kinases, and their higher expression is associated with poor survival in TNBC patients. However, there are no FDA-approved eEF2K and AXL-targeted therapeutics. To co-target these kinases, we analyzed miRNA databases and recently, we discovered that miR-329-3p has a specific binding site at both 3’-UTRs of eEF2K and AXL mRNAs. Analyzing the TCGA TNBC database, we found that low expression of miR-329-3p is correlated with shorter overall survival in TNBC patients, and the expression of miR-329-3p is reduced or lost in TNBC patient tumors. We have also developed magnetic iron-oxide-based nanoparticles (MNPs) for the delivery of miR-329-3p.
Results
We showed that miR-329-3p significantly suppresses cell proliferation, invasion, and migration by targeting both eEF2K and AXL and their downstream mediators such as SRC/FAK, and Cyclin D1 in TNBC cell lines. In vivo systemic treatment with MNPs-miR-329 completely blocks tumor growth in orthotopic TNBC xenograft models in mice. Analysis of tumors shows remarkable inhibition in eEF2K and AXL expression, and SRC, FAK, and Cyclin D1. miR-329 nanotherapy induces apoptosis and inhibits intratumoral proliferation in TNBC tumors in mice. Toxicity markers in mouse blood samples show that miR-329 nanotherapy is safe and not toxic to mice.
Conclusions
Taken together, our study suggests that miR-329-3p nanotherapy may be used as a novel potential therapeutic approach in TNBC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.