Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex vivo-cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof of principle for FEN1 blockade in tamoxifen-resistant breast cancer. SIGNIFICANCE: These findings show that pharmacologic inhibition of FEN1, which is predictive of outcome in tamoxifen-treated patients, effectively blocks ERα function and inhibits proliferation of tamoxifen-resistant tumor cells.

中文翻译：

---

核酸内切酶 FEN1 协同调节 ERα 活性并为他莫昔芬耐药的乳腺癌提供新的药物界面。

雌激素受体α (ERα) 是大多数乳腺癌的关键转录调节因子。ERα 阳性患者经常接受他莫昔芬治疗，但耐药性很常见。在这项研究中，我们改进了先前确定的 111 基因结果预测分类器，揭示 FEN1 是 ERα 阳性患者预后的最强决定因素。FEN1 水平可预测他莫昔芬治疗患者的结果，并且 FEN1 在 ERα 驱动的细胞生长中起因果作用。FEN1 通过促进共激活因子募集到 ERα 转录复合物来影响 ERα 的转录活性。FEN1 阻断诱导蛋白酶体介导的活化 ERα 降解，导致 ERα 驱动基因表达的丧失并根除肿瘤细胞增殖。最后，一个高吞吐量的 465，195 化合物筛选鉴定出一种新型 FEN1 抑制剂，可有效阻断 ERα 功能并抑制他莫昔芬耐药细胞系以及体外培养的 ERα 阳性乳腺肿瘤的增殖。总的来说，这些结果为他莫昔芬抗性乳腺癌中 FEN1 阻断的原理提供了治疗证据。意义：这些发现表明 FEN1 的药理抑制作用可预测他莫昔芬治疗患者的预后，可有效阻断 ERα 功能并抑制他莫昔芬耐药肿瘤细胞的增殖。