In a significant advancement in breast cancer research, Dr. Yongmei Yin and her team from The First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital published the article "Unveiling Alterations of Epigenetic Modifications and Chromatin Architecture Leading to Lipid Metabolic Reprogramming during the Evolutionary Trastuzumab Adaptation of HER2-Positive Breast Cancer" in Advanced Science on May, 2024. This pivotal study investigates the epigenetic and chromatin structural changes that lead to metabolic reprogramming during the development of trastuzumab resistance in HER2-positive breast cancer. HER2-positive breast cancer is characterized by the overexpression of the HER2 protein, which promotes the growth of cancer cells. Trastuzumab, a monoclonal antibody, targets the HER2 protein but is met with resistance in many patients over time. This study addresses the urgent need to understand the underlying mechanisms of trastuzumab resistance to improve treatment strategies.The study aimed to uncover how epigenetic modifications and chromatin architecture changes contribute to metabolic reprogramming in trastuzumab-resistant breast cancer cells. This comprehensive analysis included transcriptomic, epigenomic, and 3D genome architecture data from both trastuzumab-sensitive and secondary trastuzumab-resistant breast cancer cells.
The study involved comparing trastuzumab-sensitive SKBR3 cells with secondary trastuzumab-resistant SKBR3_HR cells, as well as primary trastuzumab-resistant JIMT1 cells. Key aspects of the study included:
- Gene Expression Variations: Significant changes in global gene expression were observed, with 2479 downregulated and 2069 upregulated genes during resistance formation.
- Metabolic Pathway Activity: Alterations in key metabolic pathways, particularly those related to lipid metabolism, were identified. Increased activity in pathways involving unsaturated fatty acids (UFAs) and arachidonic acid metabolism was noted.
- Epigenetic Modifications: Changes in histone modifications, particularly H3K27me3 and H3K4me3, at promoter regions were found to drive gene expression changes. The study highlighted the role of these modifications in regulating lipid metabolism.
- 3D Genome Architecture: Alterations in chromatin structure, including changes in topologically associating domains (TADs) and chromatin loops, were observed, influencing gene regulation.
The trial’s results demonstrated significant findings in the context of trastuzumab resistance:
- Gene Expression and Metabolic Reprogramming: Variations in gene expression included upregulation of genes associated with protein synthesis and immune response, and downregulation of genes involved in cell cycle and chromosomal structure. Metabolic reprogramming was evident, particularly in lipid metabolism pathways.
- Epigenetic Modifications: Significant alterations in H3K27me3 and H3K4me3 modifications at promoter regions were identified. These modifications were associated with changes in gene expression crucial for lipid metabolism, such as the upregulation of PTGS1 and PTGES and the downregulation of SCD.
- Chromatin Architecture: Changes in 3D genome architecture included increased short-range chromatin interactions and reorganization of TADs and chromatin loops. These structural changes were correlated with alterations in gene expression and enhancer-promoter interactions.
Figure 1. Establishment of secondary trastuzumab-resistant cells. a) Experimental design for the establishment of secondary trastuzumab-resistant cell. SKBR3 cells were treated with trastuzumab from 1 to 20 ug ml−1 concentration in 30 weeks period, while SKBR3 and JIMT1 cells were cultured in normal conditions for 30 weeks were considered as control. b) Viability of three cell typesindifferent trastuzumab concentrations. c) Variant expression of genes during secondary trastuzumab-resistance formation (Padj < = 0.05 & |log2 foldchange|> = 0.5 is defined as significant change). d) KEGG pathway enrichment of upregulated and downregulated genes during secondary trastuzumab-resistance formation. e) GO cellular component enrichment of upregulated and downregulated genes during secondary trastuzumab-resistance formation.
（Adv Sci (Weinh) . 2024 May;11(18):e2309424. doi: 10.1002/advs.202309424.）
Conclusion
The study by Dr. Yongmei Yin and her team provides robust evidence that epigenetic modifications and changes in chromatin architecture play critical roles in the metabolic reprogramming associated with trastuzumab resistance in HER2-positive breast cancer. These findings offer valuable insights into the mechanisms of drug resistance and highlight potential targets for improving therapeutic strategies. The research underscores the importance of understanding the interplay between epigenetics and 3D genome organization in cancer evolution and treatment adaptation.
