Repeat element-anchored enhancer-promoter interactions (REEPIs) shape the regulatory landscape of hormone-resistant breast cancer

Abstract

Repeat elements (REs) comprise over half of the human genome and are increasingly recognized as regulatory components, yet their role in therapy resistance remains unclear. Here, we integrate CAGE and RADICL-seq to map regulatory elements and RNA-chromatin interactions in estrogen receptor-positive breast cancer cells (MCF7) and their long-term estrogen-deprived (LTED) derivatives. We identify repeat element-anchored enhancer-promoter interactions (REEPIs), defined by the presence of annotated REs at both enhancer and promoter sites. In LTED cells, REEPIs are enriched for ERV1 and ERVL elements and involve specific repeat pairings associated with transcription factor combinations such as SP1-SMAD3 and SP1-NFYC. At the gene level, these REEPIs are preferentially linked to genes involved in chromatin remodeling, DNA repair, and lineage plasticity. Our findings reveal a repeat-guided regulatory architecture associated with transcriptional adaptation in endocrine resistance and identify REEPIs as a previously underexplored component of regulatory reprogramming in hormone-resistant breast cancer.