State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
Cardiothoracic Surgery Department, Characteristic Medical Center of the Chinese People's Armed Police Force, Tianjin 300162, China.
Biomolecules. 2024 Aug 30;14(9):1088. doi: 10.3390/biom14091088.
Breast cancer (BC) is the most frequently diagnosed cancer and the primary cause of cancer-related mortality in women. Treatment of triple-negative breast cancer (TNBC) remains particularly challenging due to its resistance to chemotherapy and poor prognosis. Extensive research efforts in BC screening and therapy have improved clinical outcomes for BC patients. Therefore, identifying reliable biomarkers for TNBC is of great clinical importance. Here, we found that tyrosine aminotransferase (TAT) expression was significantly reduced in BC and strongly correlated with the poor prognosis of BC patients, which distinguished BC patients from normal individuals, indicating that TAT is a valuable biomarker for early BC diagnosis. Mechanistically, we uncovered that methylation of the promoter was significantly increased by DNA methyltransferase 3 (DNMT3A/3B). In addition, reduced TAT contributes to DNA replication and cell cycle activation by regulating homologous recombination repair and mismatch repair to ensure genomic stability, which may be one of the reasons for TNBC resistance to chemotherapy. Furthermore, we demonstrated that Diazinon increases expression as an inhibitor of DNMT3A/3B and inhibits the growth of BC by blocking downstream pathways. Taken together, we revealed that is silenced by DNMT3A/3B in BC, especially in TNBC, which promotes the proliferation of tumor cells by supporting DNA replication, activating cell cycle, and enhancing DNA damage repair. These results provide fresh insights and a theoretical foundation for the clinical diagnosis and treatment of BC.
乳腺癌（BC）是最常见的癌症，也是女性癌症相关死亡的主要原因。由于三阴性乳腺癌（TNBC）对化疗的耐药性和预后不良，其治疗仍然极具挑战性。BC 筛查和治疗的广泛研究努力改善了 BC 患者的临床结果。因此，鉴定 TNBC 的可靠生物标志物具有重要的临床意义。在这里，我们发现酪氨酸转氨酶（TAT）的表达在 BC 中显著降低，并且与 BC 患者的不良预后强烈相关，这将 BC 患者与正常个体区分开来，表明 TAT 是早期 BC 诊断的有价值的生物标志物。在机制上，我们发现 DNA 甲基转移酶 3（DNMT3A/3B）显著增加了启动子的甲基化。此外，TAT 的减少通过调节同源重组修复和错配修复来促进 DNA 复制和细胞周期激活，以确保基因组稳定性，这可能是 TNBC 对化疗耐药的原因之一。此外，我们证明了敌百虫作为 DNMT3A/3B 的抑制剂增加了 的表达，并通过阻断下游途径抑制 BC 的生长。总之，我们揭示了 DNMT3A/3B 在 BC 中沉默了 ，特别是在 TNBC 中，它通过支持 DNA 复制、激活细胞周期和增强 DNA 损伤修复来促进肿瘤细胞的增殖。这些结果为 BC 的临床诊断和治疗提供了新的见解和理论基础。
