Unveiling alterations of epigenetic modifications and chromatin architecture leading to lipid metabolic reprogramming during the evolutionary trastuzumab adaptation of HER2-positive breast cancer [Cut & Tag]

Secondary trastuzumab resistance represents an evolutionary adaptation of HER2-positive breast cancer during anti-HER2 treatment. Most current studies have uncovered the alternations of HER2 and associated signaling pathways but pay less attention to broader cellular processes and their relevant genetic and epigenetic mechanisms. Here we have not only characterized transcriptome data but also examined epigenomic and 3D genome architecture information in both trastuzumab-sensitive and secondary-resistant breast cancer cells. Our findings reveal that the global metabolic reprogramming associated with trastuzumab resistance may stem from genome-wide alterations in both histone modifications and chromatin structure. Specifically, the transcriptional activities of key genes involved in lipid metabolism appear to be regulated by variant promoter H3K27me3 and H3K4me3 modifications, as well as promoter-enhancer interactions. These discoveries offer valuable insights into how cancer cells adapt to anti-tumor drugs and have the potential to impact future diagnostic and treatment strategies. Overall design: To investigate the gene expression changes of HER2 positive breast cancer cells during secondary trastuzumab resistance formation, we treated SKBR3 cells with raising trastuzumab concentration in 30 weeks.