NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis.
NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis.
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NDRG1 在侵袭性乳腺癌进展和脑转移中的作用。
DOI：
10.1093/jnci/djab222
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Debeb,BisratG
中科院分区：
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作者：
Villodre,EmillyS;Hu,Xiaoding;Eckhardt,BedrichL;Larson,Richard;Huo,Lei;Yoon,EsterC;Gong,Yun;Song,Juhee;Liu,Shuying;Ueno,NaotoT;Krishnamurthy,Savitri;Pusch,Stefan;Tripathy,Debu;Woodward,WendyA;Debeb,BisratG
背景N-Myc下游调节基因1（NDRG 1）抑制包括乳腺癌在内的多种人类恶性肿瘤的转移，但与炎性乳腺癌患者的生存率降低相关。NDRG 1在侵袭性乳腺癌的病理生物学中的作用仍然难以捉摸。MethodsTo研究NDRG 1在体内肿瘤生长和脑转移中的作用，我们将细胞移植到清除的乳腺脂肪垫中或将它们注射到SCID/Beige小鼠的尾静脉中（每组n = 7-10）。通过免疫组化染色评估患者乳腺肿瘤（n = 216）中NDRG 1蛋白的表达。采用Kaplan-Meier方法和双侧对数秩检验分析NDRG 1与至事件发生时间结局之间的相关性。多变量考克斯回归模型用于确定独立的预后因素。所有的统计检验都是2-sided.ResultsWe产生了新的亚系，表现出明显的倾向转移到大脑。NDRG 1高表达细胞在小鼠中产生更普遍的脑转移（100%vs NDRG 1低亚系的44.4%，P= 0.01，Fisher精确检验）、更大的肿瘤负荷和降低的存活率。在侵袭性乳腺癌细胞系中，沉默NDRG 1导致迁移、侵袭和肿瘤起始细胞亚群减少。在异种移植物模型中，耗尽NDRG 1抑制原发性肿瘤生长和脑转移。在乳腺肿瘤患者中，NDRG 1与侵袭性相关：NDRG 1高表达还与较短的总生存期（风险比[HR] = 2.27，95%可信区间[95%CI] = 1.20 - 4.29，P = 0.009）和乳腺癌特异性生存期（HR = 2.19，95%CI = 1.07 - 4.48，P = 0.03）相关。多变量分析显示NDRG 1是总生存期的独立预测因子（HR = 2.17，95%CI = 1.10 - 4.30，P = 0.03）和乳腺癌特异性生存率（HR = 2.27，95% CI = 1.05至4.92，P= .04）。结论我们证明NDRG 1驱动侵袭性乳腺癌的肿瘤进展和脑转移，NDRG 1高表达与较差的临床结局相关，提示NDRG 1可作为侵袭性乳腺癌的治疗靶点和预后生物标志物。
BackgroundN-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.MethodsTo study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided.ResultsWe generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high–expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines,P= .01, Fisher’s exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29,P= .009) and breast cancer–specific survival (HR = 2.19, 95% CI = 1.07 to 4.48,P= .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30,P= .03) and breast cancer–specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92,P= .04).ConclusionsWe demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.