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Science:雌激素受体(ER)阳性乳腺癌抵抗PI3K抑制剂疗法的原因

2017-03-24 Leo.C MedSci原创

KMT2D甲基转移酶原本受到PI3K信号通路中的AKT蛋白的抑制,当使用PI3K抑制剂后,AKT的活性下降,从而使KMT2D甲基转移酶的功能上升

PIK3CA基因的活化性突变在雌激素受体(ER)阳性的乳腺癌中,是十分常见的。因此PI3K信号通路的激活对于乳腺癌细胞的癌变有重要作用。因此,针对PI3K的抑制剂对于具有PIK3CA基因的活化性突变的雌激素受体(ER)阳性的乳腺癌的病人有一定的抗癌疗效。然而,用药后出现的各种抗药反应是这种疗法的疗效收到了一定的限制。使用PI3K的抑制剂后,发现各种的受雌激素受体调节的基因的表达上升,需要结合使用雌激素受体抗体来抑制这些基因的表达。也应此,结合使用雌激素受体抗体与PI3K的抑制剂对于治疗雌激素受体(ER)阳性的乳腺癌的病人有更好的疗效。然而,为什么使用PI3K的抑制剂会激活更多的癌变基因的表达呢?

在这一期的Science杂志中,Eneda Toska及其同事报道了他们最新的发现。对于雌激素受体(ER)阳性的癌细胞线使用了PI3K抑制剂后,发现了有更多的雌激素受体结合在染色体上,从而增强了下游基因的转录。研究者进一步发现,原来使用了PI3K抑制剂后,造车了一定程度的染色体素的结构变化,使更多的DNA暴露出来从而结合了更多的转录因子的。而造成这一染色体组结构变化的原因是一种叫做KMT2D的甲基转移酶的活性增强,而它的作用是去除染色体组上特定位点的甲基,从而使DNA从组蛋白(histone)的绑定中解开部分,以供转录因子结合转录基因。这一类的KMT2D甲基转移酶原本受到PI3K信号通路中的AKT蛋白的抑制,当使用PI3K抑制剂后,AKT的活性下降,从而使KMT2D甲基转移酶的功能上升。

研究者还发现,如果通过基因编辑方法抑制KMT2D甲基转移酶,则能够抑制雌激素受体(ER)所调控的基因的表达,从而抑制乳腺癌细胞的增殖。此项研究揭示了抑制PI3K信号通路对乳腺癌细胞的基因组的结构调整,说明了KMT2D甲基转移酶在促进癌细胞增殖生长,以及抵抗PI3K抑制剂的分子机理,为下一步新的治疗方案提供了理论基础。

原始出处:
Eneda Toska, Hatice U. Osmanbeyolu, Pau Castel et al.PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science 24 Mar 2017: Vol. 355, Issue 6331, pp. 1324-1330 DOI: 10.1126/science.aah6893

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    2017-08-19 jklm09
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    2017-03-26 jichang
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Breast Cancer Res:香港学者称,晚10点后吃饭或增乳腺癌风险

夜宵,灯光,常常让人感觉生活很美好。不过近期香港学者进行的一项研究显示,经常夜宵或会增加女士得乳腺癌的风险,尤其是那些苗条的、夜宵还多是主食的以及长期吃夜宵的女士风险更高。

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