Evolution of microRNA Regulation and Advancement of Delivery Systems for Multi-Target Gene Control in Breast Cancer
Background
Breast cancer is a refractory disease and a leading cause of cancer-related mortality among women. It exhibits heterogeneity, with varying genetic characteristics of cancer cells among patients, making it difficult to cure due to resistance to existing treatments and metastasis to other organs. As molecular biology has advanced, the traditional approach of developing single-target anticancer drugs has reached its limits. This is because tumor development and progression result from complex network interactions rather than individual genes. Therefore, there is a growing need for new molecular targets capable of simultaneously modulating the complex signaling pathways in tumors. Recently, the academic community has increasingly focused on microRNA (microRNA, miRNA), which finely regulates gene expression at the post-transcriptional level within cells. miRNA plays a central regulatory role in various processes, including cell proliferation, apoptosis, and the invasion of cancer cells into surrounding tissues. Active research is underway to overcome the limitations of existing drug treatments by artificially modulating the expression of this small molecule.
Key Findings
This study systematically elucidated the biological mechanisms of miRNAs that act as oncogenic or tumor-suppressive genes during breast cancer development and metastasis. The research team focused on the specific signaling pathways through which miRNAs regulate cancer cell proliferation, evasion of apoptosis, and angiogenesis. In particular, they uncovered the gene networks controlling epithelial-mesenchymal transition (EMT) and invasion, processes through which cancer cells acquire migratory abilities. The methodologies for miRNA-based gene regulation for therapeutic purposes were also comprehensively validated. To enhance miRNA function, strategies such as gene expression vectors and synthetic miRNA mimics were employed, while CRISPR activation (CRISPRa) was used to promote endogenous miRNA production in cells. Conversely, to suppress abnormally overexpressed miRNAs, anti-microRNA oligonucleotides (AMOs) and miRNA sponge technology were applied. Additionally, a precise control system was established using CRISPR-Cas9 for gene knockout and CRISPR interference (CRISPRi) to block the transcription of specific miRNAs. Performance comparisons were conducted between viral vector-based gene delivery systems and non-viral systems, including organic and inorganic nanocarriers. Organic nanocarriers based on lipid nanoparticles and polymer-based materials offer excellent biocompatibility, reducing toxicity and improving in vivo delivery efficiency. Inorganic nanocarriers, such as metal or silica-based materials, demonstrated structural stability and advantages in targeted ligand binding to specific cancer cells.
Significance and Prospects
miRNA-based breast cancer therapies are expected to expand the paradigm of precision medicine from single-target approaches to multi-network regulation. By controlling the complex tumor microenvironment from multiple angles, it may be possible to suppress the acquisition of drug resistance by cancer cells. However, several challenges must be overcome before clinical application. Research to minimize side effects caused by off-target effects is essential, as is the development of technologies to maintain effective concentrations of miRNA regulatory substances in the body without degradation until they reach the tumor tissue. For commercialization, follow-up studies are required to reduce the potential for immune responses from nanocarriers and to standardize large-scale production processes. In the future, the integration of personalized drug prescriptions based on individual miRNA profiles into precision oncology is expected to play a decisive role in improving breast cancer survival rates.
Breast cancer is a highly heterogeneous malignancy that remains one of the leading causes of cancer-related mortality among women worldwide. Despite significant advances in breast cancer research and therapy, disease heterogeneity, treatment resistance, and metastatic progression remain major obstacles to effective disease management. Among the molecular regulators involved in breast cancer, microRNAs (miRNAs) have been recognized as critical post-transcriptional regulators of gene expression, functioning as either oncogenes or tumor suppressors. By modulating the expression of target RNAs, miRNAs control key biological processes involved in tumor initiation and progression, including cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition (EMT), invasion, and metastasis. To investigate miRNA function and explore their therapeutic potential, a wide range of approaches have been developed to modulate miRNA expression. These include gain-of-function strategies, like miRNA mimics, miRNA expression vectors, and CRISPR activation (CRISPRa), as well as loss-of-function approaches, including anti-miRNA oligonucleotides (AMOs), miRNA sponges, CRISPR-Cas9-mediated gene knockout, and CRISPR interference (CRISPRi). This review provides a comprehensive overview of the biological roles of miRNAs in breast cancer and discusses current technologies for miRNA modulation, their molecular mechanisms, experimental and therapeutic applications, and associated limitations. In addition, it summarizes recent advances in miRNA delivery systems, including viral vectors, organic nanoparticles, and inorganic nanocarriers, highlighting their potential to improve delivery efficiency, target specificity, and facilitate clinical translation. Finally, the review discusses future perspectives, emphasizing the transition from single-target interventions toward network-level regulation and the integration of miRNA-based strategies into precision oncology to support the development
This technology can be directly applied in clinical settings as a combination therapy for patients with refractory breast cancer who do not respond to existing anticancer drugs. For example, consider a patient whose cancer begins to metastasize during standard chemotherapy due to the development of drug resistance. Healthcare providers can approach the case by performing a tumor tissue biopsy to obtain a map of abnormally elevated oncogenic miRNAs and reduced tumor-suppressive miRNA expression. Subsequently, anti-miRNA oligonucleotides (AMOs) targeting drug resistance-inducing genes and miRNA mimics promoting cancer cell apoptosis can be delivered to the patient via lipid nanoparticles. Initiating targeted therapy is expected to reprogram the gene network, leading to the loss of metastatic ability in cancer cells and the restoration of sensitivity to previously ineffective anticancer drugs. This regulatory approach is anticipated to open a new path for customized combination therapies that overcome the limitations of existing chemotherapy.