Antiestrogen resistance in estrogen receptor positive (ER⁺) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER⁺ metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.

中文翻译：

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IGF1R信号传导通过腔内乳腺癌中的PAK2 / PIX激活来驱动抗雌激素的产生。

雌激素受体阳性（ER ⁺）乳腺癌的抗雌激素耐药性与胰岛素样生长因子1受体（IGF1R）的表达和活性增加有关。在这里，kinome siRNA筛选已鉴定出10个IGF1R介导的抗雌激素调节剂，具有临床意义。这些包括他莫昔芬抗性抑制剂BMPR1B，CDK10，CDK5，EIF2AK1和MAP2K5，以及他莫昔芬抗性诱导剂CHEK1，PAK2，RPS6KC1，TTK和TXK。p21激活的激酶2 PAK2是最强的抗性诱导剂。他莫昔芬抗性诱导基因，特别是PAK2的沉默减弱了IGF1R介导的对他莫昔芬和氟维司群的抗性。ER ⁺中PAK2的高表达一线他莫昔芬单药治疗后转移性乳腺癌患者与不良预后相关。磷酸蛋白质组学已将PAK2和与PAK相互作用的交换因子PIXα/β定义为IGF1R信号传导的下游靶标，独立于PI3K / ATK和MAPK / ERK途径。PAK2和PIXα/β调节IGF1R信号传导驱动的细胞散射。靶向PIXα/β完全模仿了PAK2沉默对抗雌激素再敏化的作用。这些数据表明PAK2 / PIX是IGF1R介导的抗雌激素抗性的效应途径。