MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• Telomeric repeat-binding factor 2 (TRF2) is crucial for telomere maintenance and is overexpressed in various cancers, presenting a therapeutic challenge.
• Targeting TRF2 is a promising strategy for cancer treatment due to its role in cancer progression.

Purpose of the Study:

• To develop a novel microRNA (miRNA)-based approach to reduce TRF2 expression for cancer therapy.
• To identify specific miRNAs that regulate TRF2 and evaluate their therapeutic potential.

Main Methods:

• High-throughput luciferase screening of 54 candidate miRNAs to identify TRF2 regulators.
• Ectopic expression of miR-182-3p in cancer cell lines (telomerase- or ALT-positive).
• In vivo studies using triple-negative breast cancer (TNBC) models and patient-derived tumor xenografts (PDTXs) treated with lipid nanoparticle (LNP)-formulated miR-182-3p.

Main Results:

• miR-182-3p was identified as a specific and potent post-transcriptional regulator of TRF2.
• Ectopic miR-182-3p expression significantly reduced TRF2 protein levels and induced DNA damage at telomeric/pericentromeric sites, activating apoptosis.
• LNPs-miR-182-3p treatment impaired tumor growth in TNBC models without adverse effects on host survival or tissues.
• LNPs-miR-182-3p demonstrated ability to cross the blood-brain barrier and reduce intracranial tumors.

Conclusions:

• miR-182-3p represents a viable therapeutic agent for reducing TRF2 expression and combating cancer.
• LNP-mediated delivery of miR-182-3p is effective against aggressive cancers, including TNBC and brain metastases.
• This miRNA-based strategy offers a potential new avenue for cancer treatment, particularly for drug-resistant and metastatic forms.