Background

HER2 plays a critical role in tumourigenesis and is associated with poor prognosis of patients with HER2-positive breast cancers. Although anti-HER2 drugs are beneficial for treating breast cancer, de novo, or acquired resistance often develops. Epigenetic factors are increasingly targeted for therapy; however, such mechanisms that interact with HER2 signalling are poorly understood.

Methods

RNA sequencing was performed to identify PHF8 targets downstream of HER2 signalling. CHIP-qPCR were used to investigate how PHF8 regulates HER2 transcription. ELISA determined cytokine secretion. Cell-based assay revealed a feed forward loop in HER2 signalling and then evaluated in vivo.

Findings

We report the synergistic interplay between histone demethylase PHF8 and HER2 signalling. Specifically, PHF8 levels were elevated in HER2-positive breast cancers and upregulated by HER2. PHF8 functioned as a coactivator that regulated the expression of HER2, markers of the HER2-driven epithelial-to-mesenchymal transition and cytokines. The HER2-PHF8-IL-6 regulatory axis was active in cell lines and in newly established MMTV-Her2/MMTV-Cre/Phf8^fl°^x/fl°^x mouse models, which revealed the oncogenic function of Phf8 in breast cancer for the first time. Further, the PHF8-IL-6 axis contributed to the resistance to trastuzumab in vitro and may play a critical role in the infiltration of T cells in HER2-driven breast cancers.

Interpretation

These findings provided informative mechanistic insight into the potential application of PHF8 inhibitors to overcome resistance to anti-HER2 therapies.

Funding

This work was supported by Carver Trust Young Investigator Award (01-224 to H.H.Q); and a Breast Cancer Research Award (to H.H.Q.).

中文翻译：

---

PHF8 和 HER2 信号传导之间的协同作用对乳腺癌发展和耐药性的贡献

背景

HER2 在肿瘤发生中发挥着关键作用，并与 HER2 阳性乳腺癌患者的不良预后相关。尽管抗 HER2 药物对治疗乳腺癌有益，但经常会产生新的耐药性或获得性耐药性。表观遗传因素越来越成为治疗的目标；然而，人们对这种与 HER2 信号传导相互作用的机制知之甚少。

方法

进行 RNA 测序以确定 HER2 信号下游的 PHF8 靶标。CHIP-qPCR 用于研究 PHF8 如何调节 HER2 转录。ELISA测定细胞因子的分泌。基于细胞的检测揭示了 HER2 信号传导中的前馈回路，然后进行体内评估。

发现

我们报告了组蛋白去甲基化酶 PHF8 和 HER2 信号传导之间的协同相互作用。具体来说，PHF8 水平在 HER2 阳性乳腺癌中升高，并受 HER2 上调。PHF8 充当调节HER2表达的共激活剂，HER2 是 HER2 驱动的上皮间质转化的标志物和细胞因子。HER2-PHF8-IL-6调节轴在细胞系和新建立的MMTV-Her2/MMTV-Cre/Phf8 ^fl ° ^x/fl ° ^x小鼠模型中活跃，这揭示了Phf8在乳腺癌中的致癌功能第一次。此外，PHF8-IL-6轴有助于体外对曲妥珠单抗的耐药性，并且可能在HER2驱动的乳腺癌中T细胞的浸润中发挥关键作用。

解释

这些发现为 PHF8 抑制剂克服抗 HER2 疗法耐药性的潜在应用提供了信息丰富的机制见解。

资金

这项工作得到了卡弗信托青年研究者奖（01-224 至 HHQ）的支持；和乳腺癌研究奖（授予总部）。