哺乳动物启用蛋白通过抑制 AKT 信号通路提高激素受体阳性乳腺癌患者对他莫昔芬的敏感性。

IF 5.7 2区 生物学 Q1 BIOLOGY
Lifang He, Chuanghong She, Sen Jiang, Zhaochang Qi, Zihao Deng, Likeng Ji, Yukun Cui, Jundong Wu
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引用次数: 0

摘要

背景:哺乳动物使能(MENA)蛋白是使能/血管舒张剂刺激磷酸蛋白(Ena/VASP)家族的成员,它调节细胞质肌动蛋白网络的组装。它在乳腺癌的侵袭、迁移以及对靶向治疗和化疗的抗药性方面发挥着重要作用。然而,它在激素受体阳性(HR+)乳腺癌患者内分泌治疗疗效中的作用尚不清楚。本研究探讨了MENA在HR+乳腺癌患者他莫昔芬治疗耐药中的作用及其内在机制:方法:采用免疫组织化学(IHC)方法估算了临床HR+乳腺癌样本(n = 119)中MENA的表达水平,以确定其与临床病理特征、他莫昔芬耐药性和生存结果的关系。采用免疫印迹(WB)和定量反转录聚合酶链反应(qRT-PCR)分析法估测他莫昔芬敏感和耐药的HR+乳腺癌细胞系中的MENA蛋白和mRNA水平。此外,还使用了CCK8、集落形成和Transwell侵袭与迁移试验来分析MENA敲除对HR+乳腺癌细胞系的生物学行为和他莫昔芬敏感性的影响。我们在裸鼠体内进行了异种移植肿瘤实验,以确定对照组和 MENA 敲除的 HR+ 乳腺癌细胞在他莫昔芬治疗存在和不存在的情况下的肿瘤生长率和他莫昔芬敏感性。此外,我们还估算了来自MENA表达水平高和低的HR+乳腺癌患者(n = 10)的器官组织在他莫昔芬治疗下的生长率:结果:与MENA表达量高的患者相比,MENA表达量低的HR+乳腺癌患者表现出他莫昔芬耐药,预后较差。单变量和多变量Cox回归分析表明,MENA表达是HR+乳腺癌患者他莫昔芬耐药的独立预测因子。与相应的对照组相比,在体外实验和体内异种移植肿瘤小鼠模型中,MENA敲除的HR+乳腺癌细胞对他莫昔芬的敏感性明显降低。此外,MENA敲除增加了HR+乳腺癌细胞的体外侵袭和迁移。MENA 低表达的 HR+ 乳腺癌组织细胞对他莫昔芬的敏感性低于 MENA 高表达的组织细胞。从机理上讲,与相应的对照组相比,MENA敲除的HR+乳腺癌细胞在接受或不接受4-OHT治疗后,P-AKT水平明显上调:本研究表明,MENA的下调通过增强AKT信号通路促进了HR+乳腺癌组织和细胞对他莫昔芬的耐药性。因此,MENA是一种很有前景的预测生物标记物,可用于确定HR+乳腺癌患者对他莫昔芬的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mammalian enabled protein enhances tamoxifen sensitivity of the hormone receptor-positive breast cancer patients by suppressing the AKT signaling pathway.

Background: Mammalian enabled (MENA) protein is a member of the enabled/vasodilator stimulated phosphoprotein (Ena/VASP) protein family, which regulates cytoplasmic actin network assembly. It plays a significant role in breast cancer invasion, migration, and resistance against targeted therapy and chemotherapy. However, its role in the efficacy of endocrine therapy for the hormone receptor-positive (HR+) breast cancer patients is not known. This study investigated the role of MENA in the resistance against tamoxifen therapy in patients with HR+ breast cancer and the underlying mechanisms.

Methods: MENA expression levels in the clinical HR+ breast cancer samples (n = 119) were estimated using immunohistochemistry (IHC) to determine its association with the clinicopathological features, tamoxifen resistance, and survival outcomes. Western blotting (WB) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis was performed to estimate the MENA protein and mRNA levels in the tamoxifen-sensitive and -resistant HR+ breast cancer cell lines. Furthermore, CCK8, colony formation, and the transwell invasion and migration assays were used to analyze the effects of MENA knockdown on the biological behavior and tamoxifen sensitivity of the HR+ breast cancer cell lines. Xenograft tumor experiments were performed in the nude mice to determine the tumor growth rates and tamoxifen sensitivity of the control and MENA knockdown HR+ breast cancer cells in the presence and absence of tamoxifen treatment. Furthermore, we estimated the growth rates of organoids derived from the HR+ breast cancer patients (n = 10) with high and low MENA expression levels when treated with tamoxifen.

Results: HR+ breast cancer patients with low MENA expression demonstrated tamoxifen resistance and poorer prognosis compared to those with high MENA expression. Univariate and multivariate Cox regression analysis demonstrated that MENA expression was an independent predictor of tamoxifen resistance in patients with HR+ breast cancer. MENA knockdown HR+ breast cancer cells showed significantly reduced tamoxifen sensitivity in the in vitro experiments and the in vivo xenograft tumor mouse model compared with the corresponding controls. Furthermore, MENA knockdown increased the in vitro invasion and migration of the HR+ breast cancer cells. HR+ breast cancer organoids with low MENA expression demonstrated reduced tamoxifen sensitivity than those with higher MENA expression. Mechanistically, P-AKT levels were significantly upregulated in the MENA-knockdown HR + breast cancer cells treated with or without 4-OHT compared with the corresponding controls.

Conclusions: This study demonstrated that downregulation of MENA promoted tamoxifen resistance in the HR+ breast cancer tissues and cells by enhancing the AKT signaling pathway. Therefore, MENA is a promising prediction biomarker for determining tamoxifen sensitivity in patients with HR+ breast cancer.

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来源期刊
Biology Direct
Biology Direct 生物-生物学
CiteScore
6.40
自引率
10.90%
发文量
32
审稿时长
7 months
期刊介绍: Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.
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