Long Non-Coding RNAs in HER2-Positive Breast Cancer: From Resistance Mechanisms to Translational Potential

Long non-coding RNAs (lncRNAs) have emerged as key regulators of drug resistance in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, a subtype in which both intrinsic and acquired resistance to HER2-targeted therapies remain major clinical challenges. Although mechanistic studies have begun to reveal how lncRNAs modulate signaling pathways, interact with microRNAs, and influence the tumor microenvironment, dedicated investigations in HER2-positive disease are still limited. This review synthesizes current evidence across epigenetic, transcriptional, and post-transcriptional mechanisms of resistance, including competing endogenous RNA (ceRNA) networks, RNA-binding protein interactions, and exosome-mediated intercellular communication. Particular emphasis is given to resistance-associated lncRNAs such as HOX transcript antisense RNA (HOTAIR), long intergenic non-protein coding RNA 969 (LINC00969), and growth arrest-specific 5 (GAS5), which exemplify the diverse molecular strategies underlying therapy evasion. We further discuss the emerging translational potential of lncRNAs as liquid-biopsy biomarkers, therapeutic targets for antisense oligonucleotides or CRISPR-Cas13 platforms, and cargo for HER2-targeted exosome delivery. Integrating exosomal lncRNA profiling with circulating tumor DNA (ctDNA) monitoring could enable earlier detection of resistance and inform adaptive treatment strategies. By combining mechanistic insight with translational outlook, this review positions lncRNAs as promising yet underexplored contributors to HER2-positive breast cancer drug resistance and outlines a roadmap for advancing their clinical utility. The aim of this review is to synthesize current evidence on lncRNA-mediated resistance mechanisms in HER2-positive breast cancer and to highlight translational opportunities for lncRNA-based biomarkers and therapeutic strategies.