Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) are a standard-of-care treatment in combination with endocrine therapy for hormone-receptor positive advanced breast cancer. Recent studies suggested that activation of transposable elements (TEs), leading to viral mimicry response, is one of the key mechanisms by which CDK4/6i leads to tumour inhibition in breast cancer. However, acquired resistance to CDK4/6i is frequently observed and the potential role of TEs in its development is unclear.
Here, we identified and characterized TEs that are robustly activated in patient-derived xenograft (PDX) models of acquired CDK4/6i resistance. We show that the transcriptionally activated TEs display enhancer-like functions and are enriched in genomic locations with chromatin features associated with active enhancers. Furthermore, we identify distinct TE subfamilies, namely endogenous retrovirus (ERV) long terminal repeats (LTRs), which serve as binding sites for transcription factors, including FOXA1, STAT1, TP53, ESR1 and CTCF. Using chromosome conformation capture (Hi-C and Capture Hi-C) experiments, we show that regulatory ERVs contribute to 3D genome reorganisation in CDK4/6i resistant PDXs. We find a genome-wide increase in 3D genome compartment structure, with activated ERVs enriched at strong A-type compartments and new topologically associated domain (TAD) boundaries at TE-mediated CTCF binding. Importantly, activated ERVs contact and regulate expression of distal genes by creating new 3D chromatin interactions at transcription factor binding sites, indicating potential regulatory role in CDK4/6i resistance.
Together, our results suggest that activated TEs contribute to oncogene overexpression by hijacking transcription factors to alter 3D chromatin structure in CDK4/6i resistant ER+ breast cancer.