As a selective estrogen receptor β agonist, the natural flavonoid liquiritigenin reportedly inhibits invasiveness of breast cancer cells, but its specific role and mechanism remain largely unclear. In this study, cells from the triple negative breast cancer lines MDA-MB-231 and BT549 were incubated with different concentrations of liquiritigenin. The results indicated that low concentrations had no significant cytotoxic effect, whereas high concentrations decreased viability of both MDA-MB-231 and BT549 cells. Liquiritigenin treatment also resulted in increased apoptosis and enhanced Caspase3 activity. After liquiritigenin treatment, we observed decreased invasive and migratory capacities of cells, as well as upregulated E-cadherin and downregulated N-cadherin, vimentin, and MMP9. Interestingly, liquiritigenin increased the mRNA and protein expression of breast cancer 1 (BRCA1). It also increased p21 and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) levels, accompanied by decreased cellular DNA methyltransferase (DNMT) activity and downregulation of DNMT1, DNMT3a, and DNMT3b. These findings suggest that liquiritigenin can inhibit malignant behavior of triple negative breast cancer cells by inhibiting DNMT activity and increasing BRCA1 expression and its transcriptional activity. Liquiritigenin thus may be a promising candidate for the treatment of breast cancer.

Impact statement

Triple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis and higher metastatic rates and relapse frequencies than other breast cancers. Natural flavonoid liquiritigenin reportedly inhibits invasiveness of TNBC MDA-MB-231 cells, but its specific role and mechanism remain unclear. This study administered different doses of liquiritigenin into TNBC cell lines MDA-MB-231 and BT549, and found that it hindered cell proliferation, increased apoptosis, and repressed cell invasion and migration. BRCA1 exerts multiple functions and is closely related to the occurrence and development of breast cancer. Interestingly, the mRNA and protein expression of BRCA1 increased after liquiritigenin administration. Liquiritigenin also upregulated two downstream genes of BRCA1 (p21 and DNA-damage-inducible 45 alpha), decreased cellular DNA methyltransferase (DNMT) activity, and reduced BRCA1 promoter methylation. Thus, liquiritigenin may be a promising candidate for the treatment of TNBC due to its inhibition of DNMT activity and upregulation of BRCA1.

中文翻译：

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Liquiritigenin 通过抑制三阴性乳腺癌中的 DNMT 活性和增加 BRCA1 转录活性来降低肿瘤发生。

据报道，作为一种选择性雌激素受体β激动剂，天然黄酮类甘草素可抑制乳腺癌细胞的侵袭，但其具体作用和机制仍不清楚。在这项研究中，来自三阴性乳腺癌细胞系 MDA-MB-231 和 BT549 的细胞与不同浓度的甘草素一起孵育。结果表明，低浓度没有显着的细胞毒性作用，而高浓度降低了 MDA-MB-231 和 BT549 细胞的活力。Liquiritigenin 处理还导致细胞凋亡增加和 Caspase3 活性增强。在甘草素处理后，我们观察到细胞的侵袭和迁移能力降低，以及 E-cadherin 上调和 N-cadherin、vimentin 和 MMP9 下调。有趣的是，甘草素增加乳腺癌 1 (BRCA1) 的 mRNA 和蛋白质表达。它还增加了 p21 和生长停滞以及 DNA 损伤诱导 45 α (GADD45A) 水平，伴随着细胞 DNA 甲基转移酶 (DNMT) 活性降低和 DNMT1、DNMT3a 和 DNMT3b 下调。这些发现表明甘草素可以通过抑制 DNMT 活性和增加 BRCA1 表达及其转录活性来抑制三阴性乳腺癌细胞的恶性行为。因此，甘草素可能是治疗乳腺癌的有希望的候选药物。这些发现表明甘草素可以通过抑制 DNMT 活性和增加 BRCA1 表达及其转录活性来抑制三阴性乳腺癌细胞的恶性行为。因此，甘草素可能是治疗乳腺癌的有希望的候选药物。这些发现表明甘草素可以通过抑制 DNMT 活性和增加 BRCA1 表达及其转录活性来抑制三阴性乳腺癌细胞的恶性行为。因此，甘草素可能是治疗乳腺癌的有希望的候选药物。

影响陈述

三阴性乳腺癌 (TNBC) 是一种侵袭性癌症，预后较差，转移率和复发率高于其他乳腺癌。据报道，天然黄酮类甘草素可抑制 TNBC MDA-MB-231 细胞的侵袭性，但其具体作用和机制仍不清楚。本研究将不同剂量的甘草素注入 TNBC 细胞系 MDA-MB-231 和 BT549，发现其可抑制细胞增殖、增加细胞凋亡并抑制细胞侵袭和迁移。BRCA1发挥多种功能，与乳腺癌的发生发展密切相关。有趣的是，施用甘草素后 BRCA1 的 mRNA 和蛋白质表达增加。甘草素还上调了 BRCA1 的两个下游基因（p21 和 DNA 损伤诱导型 45 α），降低细胞 DNA 甲基转移酶 (DNMT) 活性，降低 BRCA1 启动子甲基化。因此，甘草素可能是治疗 TNBC 的有希望的候选药物，因为它抑制 DNMT 活性和上调 BRCA1。