Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua 500, Taiwan.
Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan.
Phytomedicine. 2021 Jan;81:153437. doi: 10.1016/j.phymed.2020.153437. Epub 2020 Dec 9.
Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The current therapeutic strategy for patients with this subtype is the use of cytotoxic chemotherapy and surgery. Luteolin is a natural herbal flavonoid and a potential therapeutic candidate for multiple diseases. The use of a treatment that combines Chinese herbal medicine and western medicine is rising in Asia.
The present study evaluates the effects and molecular mechanisms involved with luteolin treatment and evaluates whether this herb affects androgen receptor-positive breast cancer cell proliferation or metastasis.
In vitro evaluation of the effect of luteolin on androgen receptor-positive TNBC cell proliferation and metastasis METHODS: Cell viability analysis was used for the cytotoxicity test. Colony formation and Bromodeoxyuridine (BrdU) staining-based proliferation experiments were used for cell proliferation. Wound healing and transwell assays were used for in vitro migration/invasion. The RT-qPCR analysis was used for gene expression. Furthermore, ChIP-qPCR analysis was used for epigenetic modification of gene promoters.
Luteolin significantly inhibited the proliferation and metastasis of androgen receptor-positive TNBC. Furthermore, luteolin inactivated the AKT/mTOR signaling pathway and reversed the epithelial-mesenchymal transition (EMT). The combination of luteolin and inhibitors of AKT/mTOR synergistically repressed an androgen receptor-positive TNBC cell proliferation and metastasis. Luteolin also downregulated MMP9 expression by decreasing the levels of the AKT/mTOR promoting H3K27Ac and H3K56A on the MMP9 promoter region.
Our findings indicate that luteolin inhibited the proliferation and metastasis of androgen receptor-positive TNBC by regulating MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K27Ac and H3K56Ac.
三阴性乳腺癌（TNBC）占所有乳腺癌的 20%。这种癌症缺乏雌激素受体、孕激素受体和人表皮生长因子受体 2 的表达。目前，治疗这种亚型患者的策略是使用细胞毒性化疗和手术。木犀草素是一种天然草药类黄酮，是多种疾病的潜在治疗候选药物。亚洲联合使用中药和西药的治疗方法正在增加。
本研究评估了木樨草素治疗的效果和所涉及的分子机制，并评估了这种草药是否会影响雄激素受体阳性乳腺癌细胞的增殖或转移。
体外评估木樨草素对雄激素受体阳性 TNBC 细胞增殖和转移的影响
细胞活力分析用于细胞毒性试验。集落形成和溴脱氧尿苷（BrdU）染色增殖实验用于细胞增殖。划痕愈合和 Transwell 测定用于体外迁移/侵袭。RT-qPCR 分析用于基因表达。此外，ChIP-qPCR 分析用于基因启动子的表观遗传修饰。
木樨草素显著抑制了雄激素受体阳性 TNBC 的增殖和转移。此外，木樨草素抑制了 AKT/mTOR 信号通路并逆转了上皮-间充质转化（EMT）。木樨草素与 AKT/mTOR 抑制剂联合使用可协同抑制雄激素受体阳性 TNBC 细胞的增殖和转移。木樨草素还通过降低 AKT/mTOR 促进 MMP9 启动子区域 H3K27Ac 和 H3K56A 的水平来下调 MMP9 的表达。
我们的研究结果表明，木樨草素通过降低 AKT/mTOR 诱导的 H3K27Ac 和 H3K56A 水平来调节 MMP9 的表达，从而抑制雄激素受体阳性 TNBC 的增殖和转移。
