PDF(Pubmed)
Abstract：
Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated efficacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes (ar, cdkn1a, erbb2, esr1, hsp90aa1) and seven drug-disease crossover genes (cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll) were identified using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and -sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin\'s specific impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.
摘要：
乳腺癌是全球女性癌症相关死亡的主要原因，激素受体(HR)+是主要亚型。他莫昔芬(TAM)作为HR+乳腺癌的主要治疗方法。然而,耐药性往往导致复发，强调需要开发新的疗法来提高患者的生活质量和降低复发率。青蒿素（ART）已证明在抑制耐药细胞生长方面的功效，将艺术定位为抵消内分泌抵抗的可行选择。本研究通过生物信息学分析和实验验证相结合的方法探索了青蒿素和他莫昔芬之间的相互作用。五个特征基因(AR，cdkn1a,erbb2，esr1，hsp90aa1）和七个药物-疾病交叉基因（cyp2e1，rorc，mapk10,glp1r,egfr,PGR,mgll)使用WGCNA交叉分析鉴定。随后进行功能富集分析。我们的发现证实了他莫昔芬耐药和致敏患者的关键簇基因表达与免疫细胞浸润之间的显着相关性。scRNA-seq分析显示关键簇基因在上皮细胞中高表达，提示青蒿素对雌激素受体（ER）阳性BC组织中肿瘤细胞的特异性影响。分子靶标对接和青蒿素对LCC9细胞的体外实验表明，通过调节相关耐药基因，可以逆转耐药细胞的迁移和耐药。这些结果表明青蒿素可以潜在地逆转ER阳性乳腺癌中的他莫昔芬耐药性。
