Breast cancer remains one of the most prevalent diseases worldwide, primarily affecting women. Its heterogeneous nature poses a significant challenge in the development of effective and targeted treatments. Molecular characterization has enabled breast cancer to be classified into four main subtypes: luminal A, luminal B, HER2-positive, and triple-negative breast cancer, based on hormone receptor expression and HER2 status. A deeper understanding of these molecular markers and their associated signaling pathways, such as MAPK and PI3K/AKT, is essential for improving prognosis and optimizing treatment strategies. Currently, several therapeutic agents are utilized in neoadjuvant and adjuvant therapies, often in combination with surgical interventions. However, emerging evidence highlights the growing challenge of drug resistance, which significantly limits the efficacy of existing treatments. Addressing this issue may require innovative approaches, including combination therapies and precision medicine strategies, tailored to the molecular profile of each patient. Therefore, a comprehensive understanding of the pathophysiologic mechanisms driving breast cancer progression and resistance is crucial for the development of advanced targeted therapies with greater precision and efficacy. This review aims to explore recent advancements in molecular research related to breast cancer subtypes and provide a critical analysis of current therapeutic approaches within the framework of precision medicine.

HER2-low breast cancer has been recognized as a heterogenous group of tumors influenced by hormone receptor (HR) expression, giving rise to tumors with either a luminal-like phenotype or features resembling triple-negative breast cancer (TNBC). Despite the development of HER2-targeted therapies, several studies have demonstrated their limited efficacy in patients diagnosed with HER2-low breast cancer. However, recent research has led to the development of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), with the latter showing promising results in treating these patients. Despite this breakthrough, the availability of a single effective therapy fails to account for tumor heterogeneity and may contribute to the emergence of therapy resistance, leaving HER2-low patients without treatment options. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level and are capable of modulating key cellular processes. Recent studies have highlighted their potential as therapeutic targets, contributing to the advancement of personalized, patient-center therapies. In this context, the interplay between miRNAs and HER2-targeted therapies, particularly their modulation of common essential genes and signaling pathways, could reshape HER2-low therapy strategies to transform current practices aimed at improving the overall patient outcomes. Therefore, this review aims to elucidate the mechanisms underlying current HER2-targeted therapy and explore a potential crosstalk with miRNAs, ultimately serving as a guide for the development of personalized therapeutic strategies.

Background: HER2-low breast cancer is a biologically heterogeneous subgroup in which hormone receptor (HR) expression critically shapes prognosis and treatment, but the underlying regulatory mechanisms remain unclear. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and may contribute to HR heterogeneity. This study aimed to identify deregulated miRNAs and associated gene networks distinguishing HER2-low/HR-positive from HER2-low/HR-negative tumors, elucidating the molecular mechanisms underlying this divergence. Methods: Differential expression analyses of miRNAs and genes were performed using Wilcoxon tests and DESeq2 (|log₂FC| > 1; FDR-adjusted p-value < 0.05). Survival analyses were conducted using Cox proportional hazards models to evaluate the individual miRNAs and miRNA signature. Functional enrichment analyses, including GO, KEGG and Reactome pathways, were performed. Correlation analysis and the miRNA target prediction were integrated to identify regulatory interactions. Results: Comparisons between HER2-low/HR-positive and HER2-low/HR-negative tumors identified 165 significantly deregulated miRNAs and 170 strongly deregulated genes. Intersection analysis highlighted miR-9-5p, miR-532-5p and miR-576-5p as specifically associated with HR-negative status. Survival analyses showed non-significant trends for the overall survival and progression-free interval. Functional enrichment analysis revealed hormone-related pathways in HR-positive tumors and immune, inflammatory and proliferative pathways in HR-negative tumors. Integrative correlation and target prediction analyses identified two miRNA–mRNA regulatory axes, miR-576-5p/TGFBI and miR-9-5p/POU2F2. Conclusions: Our study demonstrated that HER2-low breast cancer exhibits distinct miRNA and gene expression profiles, which highlight different transcriptomic profiles according to HR status for the first time. Specific miRNA–gene networks may drive transcriptional heterogeneity, serving as potential biomarkers for stratification and as therapeutic targets. These findings provide insight into the molecular basis of HER2-low tumor diversity and support future development of HR-directed therapeutic strategies.