The Role of miR-21 in HER2-Positive Breast Cancer: A Comprehensive Review of Molecular Mechanisms, Biomarker Potential, and Therapeutic Implications

Breast cancer continues to be the most prevalent cancer affecting women, with Human Epidermal Growth Factor Receptor 2-positive (HER2-positive) breast cancer presenting particular difficulties because of its aggressive nature and resistance to treatments aimed at specific targets. MicroRNA-21 (miR-21) has been identified as an important factor in controlling HER2-related cancer development, significantly contributing to tumor growth, spread, and resistance to therapy. miR-21 is upregulated by approximately 2-5-fold in HER2-positive tumors compared to HER2-negative tumors, as reported in several clinical studies, correlating with advanced disease stage, lymph node metastasis, and resistance to HER2-targeted therapies. This study explores the multifaceted contributions of miR-21 to HER2-positive breast cancer biology, emphasizing its regulatory role in key oncogenic pathways, including PI3K/AKT/mTOR and MAPK/ERK. Here, discuss the possibility of miR-21 as a biomarker for diagnosis, prognosis, and monitoring therapeutic responses, particularly in liquid biopsy formats such as serum and extracellular vesicles (EVs). Furthermore, this review examines promising therapeutic strategies targeting the miR-21/HER2 axis, highlighting ongoing preclinical developments and future clinical applications. Despite the challenges in standardizing miR-21-based diagnostics and therapies, this review highlights the increasing potential of miR-21 as a therapeutic target, particularly in overcoming resistance to HER2-targeted treatments. This offers a promising pathway toward more personalized and effective options for HER2-positive breast cancer. However, while miR-21 shows significant promise, no therapies targeting miR-21 have been approved for clinical use, emphasizing the need for further research and clinical trials.