Cullin7 enhances resistance to trastuzumab therapy in Her2 positive breast cancer via degrading IRS-1 and downregulating IGFBP-3 to activate the PI3K/AKT pathway
Cullin7 enhances resistance to trastuzumab therapy in Her2 positive breast cancer via degrading IRS-1 and downregulating IGFBP-3 to activate the PI3K/AKT pathway
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Cullin7 通过降解 IRS-1 和下调 IGFBP-3 激活 PI3K/AKT 通路，增强 Her2 阳性乳腺癌对曲妥珠单抗治疗的耐药性
DOI：
10.1016/j.canlet.2019.08.008
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Li, Hong-sheng
中科院分区：
文献类型：
--
作者：
Qiu, Ni;He, Yu-fang;Li, Hong-sheng
Her 2阳性乳腺癌患者在Her 2靶向治疗后不到一年内表现出新发耐药或获得性耐药，但其机制尚未完全阐明。补偿途径如IGF-1 R/IRS-1途径被激活，导致PI 3 K/Akt/mTOR途径活性异常增强，从而减弱曲妥珠单抗的疗效。Cullin 7以mTOR/S6 K依赖的方式参与IRS-1的降解。Cullin 7是否参与曲妥珠单抗耐药还需进一步研究。在这里，我们揭示了Cullin 7在曲妥珠单抗耐药Her 2阳性乳腺癌细胞中过表达。Cullin 7的敲低减少IRS-1的Ser磷酸化的降解，减弱PI 3 K/AKT通路的激活，并部分恢复曲妥珠单抗耐药Her 2阳性乳腺癌细胞中的曲妥珠单抗敏感性。IGFBP-3表达在曲妥珠单抗耐药Her 2阳性乳腺癌细胞中降低，这导致Wnt信号通路抑制的释放和Cullin 7表达的增加，如TCF 7 L2所介导的。Cullin 7在Her 2扩增的乳腺癌组织中的过表达具有临床意义，因为它与较短的无病生存期（DFS）和对曲妥珠单抗的反应不足呈正相关。因此，我们的研究结果表明Cullin 7在曲妥珠单抗应答中的关键作用，这对选择Her 2阳性乳腺癌的最佳治疗策略具有重要意义。
Patients with Her2-positive breast cancer exhibit de novo resistance or develop acquired resistance in less than one year after Her2 targeting treatment, but the mechanism is not fully elucidated. Compensatory pathways such as the IGF-1R/IRS-1 pathway, are activated, leading to aberrant enhanced PI3K/Akt/mTOR pathway activity to attenuate the efficacy of trastuzumab. Cullin7 could participate in the degradation of IRS-1 in a mTOR/S6K dependent manner. Whether Cullin7 participates in trastuzumab resistance needs to be further investigated. Here, we reveals that Cullin7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells. Knockdown of Cullin7 reduces degradation of Ser phosphorylation of IRS-1, attenuates activation of the PI3K/AKT pathway, and partly restores trastuzumab sensitivity in trastuzumab-resistant Her2 positive breast cancer cells. IGFBP-3 expression is decreased in trastuzumab-resistant Her2 positive breast cancer cells, which leads to release of the Wnt signaling pathway inhibition and an increase in Cullin7 expression, as mediated by TCF7L2. Overexpression of Cullin7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers.