KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer
KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer
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KLF4通过抑制MAPK信号通路克服他莫昔芬耐药并预测乳腺癌的良好预后
DOI：
10.1016/j.cellsig.2017.09.025
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发表时间：
2018-01-01
影响因子：
4.8
通讯作者：
Wang, Linbo
中科院分区：
文献类型：
--
作者：
Jia, Yunlu;Zhou, Jichun;Wang, Linbo
他莫昔芬耐药性对乳腺癌的成功治疗构成了严峻的挑战。 Kruppel样因子4在乳腺癌的发生和进展中发挥着关键作用，但其表达、功能以及对乳腺癌TAM治疗疗效的调节仍有待研究。在这里，我们研究了 KLF4 在乳腺癌中的临床意义和生物学效应。首先，KLF4的高表达与乳腺癌细胞中TAM敏感性的增加相关，GEO数据集的分析表明KLF4的表达与ERα呈正相关，并且KLF4的表达增强使乳腺癌患者对内分泌治疗敏感。 MCF-7 和 BCAP37 细胞中 KLF4 的敲低导致 TAM 耐药性增加，而异位 KLF4 表达则促进 T47D 和 TAM 耐药性 MCF-7/TAM 细胞对 TAM 的反应。其次，异位KLF4过表达抑制MCF-7/TAM细胞的生长、侵袭和迁移。此外，KLF4 表达在乳腺癌肿瘤组织中下调，KLF4 的高表达与良好的预后相关。从机制上讲，KLF4可能通过抑制丝裂原激活蛋白激酶（MAPK）信号通路来增强乳腺癌细胞对TAM的反应性。我们发现，与 MCF-7 相比，MCF-7/TAM 中的 ERK 和 p38 更加活化，并且使用 MAPK 特异性抑制剂治疗可显着抑制细胞活力。 KLF4 的敲低激活了 ERK 和 p38，并驱使 MCF-7 细胞对 TAM 产生抗性。相反，MCF-7/TAM 细胞中 KLF4 的过度表达会抑制 ERK 和 p38 信号传导，并导致对 TAM 的敏感性增加。因此，我们的研究结果表明，KLF4 通过 ERK 和 p38 信号传导的磷酸化修饰促进乳腺癌中的 TAM 敏感性。总的来说，这项研究强调了KLF4/MAPK信号相互作用在调节乳腺癌TAM耐药中的重要性，并表明靶向KLF4/MAPK信号可能是乳腺癌治疗的潜在治疗策略，特别是对于TAM耐药患者。
Tamoxifen resistance represents a daunting challenge to the successful treatment for breast cancer. Kruppel-like factor 4 has critical roles in the development and progression of breast cancer, but its expression, function and regulation in the efficacy of TAM therapy in breast cancer have yet to be investigated. Here, we examined the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 correlated with increased TAM sensitivity in breast cancer cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ER alpha and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness to TAM in T47D and TAM-resistant MCF-7/TAM cells. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion and migration. Moreover, KLF4 expression was down-regulated in breast cancer tumor tissues and high expression of KLF4 was associated with favorable outcomes. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and p38 were more activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors significantly suppressed cell viability. Knockdown of KLF4 activated ERK and p38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and p38 signaling and resulted in increased sensitivity to TAM. Therefore, our findings suggested that KLF4 contributed to TAM sensitivity in breast cancer via phosphorylation modification of ERK and p38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for the TAM-resistant patients.