Epigenetic and 3D Genome Changes Drive Primary Trastuzumab Resistance in HER2+ Breast Cancer

Primary trastuzumab resistance poses a significant challenge in the treatment of HER2-positive breast cancer. Despite various proposed mechanisms and responses to address this resistance, current treatments remain less effective, highlighting the need for new targets and insights. Our research, which integrates epigenomic and 3D genomic architectural data, suggests that changes in promoter modifications, specifically H3K4me3 and H3K27me3, along with differential active enhancers and promoter-enhancer interactions, may contribute to differential gene expression in trastuzumab-resistant versus sensitive cells. Notably, we identified SGK1, which lies downstream of both the PI3K-AKT and mTOR signaling pathways, exhibits overexpression associated with increased H3K4me3 signals at its promoter and enhanced promoter-enhancer interactions in trastuzumab-resistance cells. The overexpression of SGK1 supports cell survival and stimulates proliferation, making it a potential critical factor driving primary trastuzumab resistance. These discoveries provide new insights into the mechanisms underlying primary trastuzumab resistance in HER2-positive breast cancer, which may pave the way for developing more effective diagnostic and treatment strategies in the future.