TRAF6已成为乳腺癌（BCa）的关键调节因子。然而,TRAF家族由七个成员组成，它们表现出不同和重叠的功能。为了探索哪些TRAF代表BCa治疗的潜在药物靶标，我们搜索了Medline,WebofScience和Scopus从开始到2021年6月27日进行相关研究。我们在体外鉴定了14个，11个体内和4个人类文章。药理学研究的荟萃分析表明，TRAF2/4的体外抑制作用（平均差异（MD）：-57.49，95％CI：-66.95，-48.02，P<0.00001）或TRAF6（标准（Std。）MD：-4.01，95％CI：-5.75，-2.27，P<0.00001）与BCa细胞迁移减少有关。始终如一，TRAF2/4（MD：-51.08，95%CI：-64.23，-37.94，P<0.00001）和TRAF6（标准。MD：-2.80，95％CI：-4.26，-1.34，P=0.0002）与BCa细胞侵袭减少有关，而TRAF2/4抑制(MD:-40.54,95%CI:-52.83,-28.26,P<0.00001)与BCa细胞粘附减少有关。有趣的是,仅TRAF6的抑制(MD:-21.46,95%CI:-30.40,-12.51,P<0.00001)与细胞生长减少相关。在BCa的动物模型中，施用TRAF2/4的药理学抑制剂(Std.MD：-3.36，95%CI：-4.53，-2.18，P<0.00001）或TRAF6（标准。小鼠中的MD:-4.15,95%CI:-6.06,-2.24,P<0.0001)与肿瘤负荷的减少相关。相比之下,TRAF6抑制剂（MD：-2.42，95％CI：-3.70，-1.14，P=0.0002）减少BCa转移。在BCa患者中，TRAF6的高表达(危险比:1.01,CI:1.01,1.01,P<0.00001)与低生存率相关。BCa患者的临床和路径和过程富集分析的生物信息学验证证实，TRAF6的增加/扩增与骨骼中的继发性BCa相关（P=0.0079），生存率低(P<0.05)。总的来说,TRAF6抑制剂在转移性BCa的治疗中显示出希望。然而,研究数量少以及动物和人体研究的证据匮乏可能会限制将现有研究结果转化为临床实践.
TRAF6 has emerged as a key regulator of breast cancer (BCa). However, the TRAF family constitutes of seven members that exhibit distinct and overlapping functions. To explore which TRAF represents a potential druggable target for BCa treatment, we searched Medline, Web of Science and Scopus for relevant studies from inception to June 27, 2021. We identified 14 in vitro, 11 in vivo and 4 human articles. A meta-analysis of pharmacological studies showed that in vitro inhibition of TRAF2/4 (mean difference (MD): - 57.49, 95% CI: - 66.95, - 48.02, P < 0.00001) or TRAF6 (standard(Std.)MD: - 4.01, 95% CI: - 5.75, - 2.27, P < 0.00001) is associated with reduction in BCa cell migration. Consistently, inhibition of TRAF2/4 (MD: - 51.08, 95% CI: - 64.23, - 37.94, P < 0.00001) and TRAF6 (Std.MD: - 2.80, 95% CI: - 4.26, - 1.34, P = 0.0002) is associated with reduced BCa cell invasion, whereas TRAF2/4 inhibition (MD: - 40.54, 95% CI: - 52.83, - 28.26, P < 0.00001) is associated with reduced BCa cell adhesion. Interestingly, only inhibition of TRAF6 (MD: - 21.46, 95% CI: - 30.40, - 12.51, P < 0.00001) is associated with reduced cell growth. In animal models of BCa, administration of pharmacological inhibitors of TRAF2/4 (Std.MD: - 3.36, 95% CI: - 4.53, - 2.18, P < 0.00001) or TRAF6 (Std.MD: - 4.15, 95% CI: - 6.06, - 2.24, P < 0.0001) in mice is associated with reduction in tumour burden. In contrast, TRAF6 inhibitors (MD: - 2.42, 95% CI: - 3.70, - 1.14, P = 0.0002) reduced BCa metastasis. In BCa patients, high expression of TRAF6 (Hazard Ratio: 1.01, CI: 1.01, 1.01, P < 0.00001) is associated with poor survival rate. Bioinformatics validation of clinical and pathway and process enrichment analysis in BCa patients confirmed that gain/amplification of TRAF6 is associated with secondary BCa in bone (P = 0.0079), and poor survival rate (P < 0.05). Overall, TRAF6 inhibitors show promise in the treatment of metastatic BCa. However, low study number and scarcity of evidence from animal and human studies may limit the translation of present findings into clinical practice.
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