Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Natl Cancer Inst. 2022 Apr 11;114(4):579-591. doi: 10.1093/jnci/djab222.
N-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.
To 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.
We 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).
We 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.
N- Myc 下游调节基因 1（NDRG1）可抑制多种人类恶性肿瘤的转移，包括乳腺癌，但与炎性乳腺癌患者的生存预后较差有关。NDRG1 在侵袭性乳腺癌的病理生物学中的作用仍难以捉摸。
为了研究 NDRG1 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尾静脉注射到 SCID/Beige 小鼠中（每组 7-10 只）。通过免疫组织化学染色评估患者乳腺癌肿瘤中的 NDRG1 蛋白表达（n=216）。使用双侧对数秩检验的 Kaplan-Meier 方法分析 NDRG1 与生存时间相关事件之间的关系。使用多变量 Cox 回归模型确定独立的预后因素。所有统计检验均为双侧。
我们生成了新的亚系，这些亚系表现出明显向脑转移的倾向。NDRG1 高表达细胞产生更常见的脑转移（NDRG1 低亚系为 44.4%，NDRG1 高亚系为 100%，P=0.01，Fisher 确切检验）、更大的肿瘤负担和小鼠生存时间缩短。在侵袭性乳腺癌细胞系中，沉默 NDRG1 导致迁移、侵袭和肿瘤起始细胞亚群减少。在异种移植模型中，耗尽 NDRG1 抑制了原发性肿瘤生长和脑转移。在患者的乳腺癌肿瘤中，NDRG1 与侵袭性有关：NDRG1 高表达也与总生存时间更短相关（风险比[HR]=2.27，95%置信区间[95%CI]=1.20 至 4.29，P=0.009）和乳腺癌特异性生存时间（HR=2.19，95%CI=1.07 至 4.48，P=0.03）。多变量分析显示 NDRG1 是总生存时间（HR=2.17，95%CI=1.10 至 4.30，P=0.03）和乳腺癌特异性生存时间（HR=2.27，95%CI=1.05 至 4.92，P=0.04）的独立预测因子。
我们证明 NDRG1 可驱动侵袭性乳腺癌的肿瘤进展和脑转移，并且 NDRG1 高表达与更差的临床结局相关，这表明 NDRG1 可能作为侵袭性乳腺癌的治疗靶点和预后生物标志物。
