Chang C J, Chiu J H, Tseng L M, Chang C H, Chien T M, Wu C W, Lui W Y
Institute of Traditional Medicine, Veterans General Hospital, Taipei, Taiwan.
Eur J Clin Invest. 2006 Aug;36(8):588-96. doi: 10.1111/j.1365-2362.2006.01676.x.
The molecular mechanisms underlying the mitogenic effect of ferulic acid (FA), an active compound derived from Angelica sinensis, have never been elucidated. It was the aim of this study to investigate the proliferative effect of FA on human breast cancer cell lines and to elucidate its modulation mechanism on HER2 expression in MCF7 line.
By using MCF7 (oestrogen receptor-positive; ER+, HER2-low), BT474 (ER+, HER2-high), MDAMB231 (ER-, HER2-low) and SKBR3 (ER-, HER2-high) human breast cancer cell lines as in vitro models, the mitogenic effects of FA were assessed by trypan blue dye exclusion assay and DNA flow cytometry. Ferulic acid-modulated cell signalling and HER2 gene expression were evaluated in MCF7 line by Western blot and real-time RT-PCR analysis.
Ferulic acid ER-dependently stimulated cell proliferation on MCF7 cells in a concentration-dependent manner. The HER2 oncogene (one of the prognostic factors of breast cancer) and ESR1 gene (oestrogen receptor-alpha; ERalpha) transcription were markedly up-regulated by FA treatment. Besides, HER2 signalling and its downstream molecules such as AKT and ERK1/2 were involved in FA-modulated ERalpha and cyclin D1 synthesis. Addition of anti-HER2 antibody, trastuzumab, abrogated FA-enhanced proliferative effect on MCF7 cells, indicated a positive feedback control for the action of HER2 in this setting. The fact that the ER antagonist blocked most of the FA-up-regulated HER2 expression, and that trastuzumab down-regulated ERalpha gene expression, suggested a cross-talk between ERalpha and HER2 signalling on MCF7 cells.
The authors' conclude that FA causes human breast cancer cell proliferation by up-regulation of HER2 and ERalpha expression.
阿魏酸（FA）是当归中的一种活性化合物，其促有丝分裂作用的分子机制尚未阐明。本研究旨在探讨FA对人乳腺癌细胞系的增殖作用，并阐明其对MCF7细胞系中HER2表达的调节机制。
以MCF7（雌激素受体阳性；ER+，HER2低表达）、BT474（ER+，HER2高表达）、MDAMB231（ER-，HER2低表达）和SKBR3（ER-，HER2高表达）人乳腺癌细胞系作为体外模型，通过台盼蓝拒染法和DNA流式细胞术评估FA的促有丝分裂作用。通过蛋白质免疫印迹法和实时逆转录聚合酶链反应分析，在MCF7细胞系中评估阿魏酸调节的细胞信号传导和HER2基因表达。
阿魏酸以浓度依赖的方式对MCF7细胞产生雌激素受体依赖性的细胞增殖刺激作用。FA处理显著上调了HER2癌基因（乳腺癌预后因素之一）和ESR1基因（雌激素受体α；ERα）的转录。此外，HER2信号传导及其下游分子如AKT和ERK1/2参与了FA调节的ERα和细胞周期蛋白D1的合成。添加抗HER2抗体曲妥珠单抗可消除FA对MCF7细胞的增殖增强作用，表明在此情况下HER2的作用存在正反馈控制。雌激素受体拮抗剂阻断了大部分FA上调的HER2表达，而曲妥珠单抗下调了ERα基因表达，这一事实表明MCF7细胞上ERα和HER2信号传导之间存在相互作用。
作者得出结论，FA通过上调HER2和ERα表达导致人乳腺癌细胞增殖。
