未经批准:锌是一种关键的第二信使,可以调节癌细胞内的多种信号通路,因此,它的水平需要严格控制。Zrt,Irt样蛋白(ZIP,SLC39A)锌转运蛋白家族从细胞外或细胞内储存增加胞浆锌。这项研究探讨了锌转运蛋白ZIP7和ZIP6作为他莫昔芬耐药(TAMR)乳腺癌治疗靶标的相关性。
未经评估:一系列体外试验,包括免疫组织化学,免疫荧光,流式细胞术,和蛋白质印迹用于评估TAMR和敏感(MCF-7)乳腺癌模型中ZIP7和ZIP6的水平和活性。这些转运体在临床环境中的分析使用公开的在线资源进行:基因表达谱交互式分析(GEPIA)2和Kaplan-Meier绘图仪(KmPlot)。
UNASSIGNED:与反应性MCF-7细胞相比,TAMR细胞中ZIP7的总水平和活化水平均显著升高。这伴随着游离细胞质锌的相关增加,导致下游信号的放大。与我们提出的模型一致,激活的ZIP6水平与有丝分裂细胞相关,通过使用我们的抗ZIP6单克隆抗体可以有效地抑制。在两种模型中,有丝分裂抑制都转化为受损的增殖,与TAMR细胞显示增加的灵敏度。对来自患者的匹配的肿瘤和正常乳腺样本的分析显示,肿瘤中ZIP7和ZIP6的显着增加。以及家庭成员ZIP4。Kaplan-Meier分析显示,高ZIP7水平与患者总体生存率和无复发生存率(RFS)下降相关。包括接受过全身内分泌治疗或他莫昔芬治疗的患者组.相比之下,高ZIP6水平与所有患者的总体和RFS改善显着相关,以及接受全身内分泌治疗的患者的RFS。
UNASSIGNED:与抗激素反应细胞相比,TAMR细胞显示ZIP7和ZIP6转运蛋白的活性增加,表明它们在抗性疾病发展后作为新的治疗靶点的潜力。
UNASSIGNED: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer.
UNASSIGNED: A series of in vitro assays, including immunohistochemistry, immunofluorescence, flow cytometry, and western blotting were used to evaluate levels and activity of ZIP7 and ZIP6 in models of TAMR and sensitive (MCF-7) breast cancer. Analyses of these transporters in the clinical setting were performed using publicly available online resources: Gene Expression Profiling Interactive Analysis (GEPIA)2 and Kaplan-Meier Plotter (KmPlot).
UNASSIGNED: Both total and activated levels of ZIP7 were significantly elevated in TAMR cells versus responsive MCF-7 cells. This was accompanied by an associated increase in free cytoplasmic zinc leading to amplification of downstream signals. Consistent with our proposed model, activated ZIP6 levels correlated with mitotic cells, which could be efficiently inhibited through use of our anti-ZIP6 monoclonal antibody. Mitotic inhibition translated to impaired proliferation in both models, with TAMR cells displaying increased sensitivity. Analysis of matched tumour and normal breast samples from patients revealed significant increases in both ZIP7 and ZIP6 in tumours, as well as family member ZIP4. Kaplan-Meier analysis revealed that high ZIP7 levels correlated with decreased overall and relapse-free survival (RFS) of patients, including patient groups who had received systemic endocrine therapy or tamoxifen only. In contrast, high ZIP6 levels were significantly linked to improved overall and RFS in all patients, as well as RFS in patients that received systemic endocrine therapy.
UNASSIGNED: TAMR cells displayed increased activity of both ZIP7 and ZIP6 transporters compared to anti-hormone responsive cells, suggesting their potential as novel therapeutic targets following development of resistant disease.