Comprehensive analysis of retrotransposons (LTR and non-LTR) in breast cancer

Transposable elements, including human endogenous retroviruses (HERVs) and non-long terminal repeat (non-LTR) retrotransposons, are reactivated in tumors due to epigenetic dysregulation and may influence oncogenesis via gene activation or immune modulation. This study investigates locus-specific expression of HERVs and non-LTR elements in breast cancer (BC) and their clinical relevance. We conducted total RNA sequencing on 305 BC tumors and 32 matched normal tissues, followed by transcriptomic and retrotranscriptomic profiling. Telescope and TEspeX were used to quantify locus-specific expression of HERVs and non-LTR retrotransposons, respectively, using genome annotations and curated TE references. A total of 2,275 differentially expressed HERV loci were identified, 246 of which were associated with patient survival. Many overlapped cancer-related genes (e.g., ADGRB3 , CDC45 , JAK1 ), suggesting potential regulatory roles. Clustering based on these 246 HERVs defined four subgroups with distinct prognoses; higher HERV expression correlated with worse survival. These subtypes differed in clinical-genomic features, including age, hormone receptor status, diabetes, and mutations in TP53 , PIK3CA , and GATA3 . Differences in stemness, RNA transport, metabolic gene expression, and immune infiltration (e.g., Th17/Th2 vs. immunosuppressive cells) further distinguished subtypes. Additionally, one Alu non-LTR element was upregulated in tumors. Our results reveal that locus-specific HERV expression stratifies BC into biologically and clinically distinct subtypes. These findings highlight the interplay between retrotransposon activity, transcriptional programs, and immune contexture, suggesting potential applications of HERVs as biomarkers or therapeutic targets in BC.