Joshi Vaibhavi, Stacey Andrew, Feng Yufan, Kalita-de Croft Priyakshi, Duijf Pascal Hg, Simpson Peter T, Lakhani Sunil R, McCart Reed Amy E
UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
Centre for Cancer Biology, Clinical and Health Sciences, University of South Australia & SA Pathology, Adelaide, Australia.
J Pathol Clin Res. 2024 Mar;10(2):e12364. doi: 10.1002/2056-4538.12364.
Brain metastases are secondary brain tumours characterised by their aggressive nature and poor prognosis. Breast cancer is one of the most common primary tumours in women to spread to the brain. A lack of biomarkers predicting likely spread to the brain and limited therapeutic interventions represents major areas of clinical unmet need. We investigated N-myc downregulated gene-1 (NDRG1) as a clinically relevant biomarker in breast cancer brain metastasis patients. NDRG1 expression was investigated using immunohistochemistry on tissue microarrays of two clinical cohorts: (i) brain metastatic breast cancers (n = 48) and brain metastases (n = 64; including a subset of 39 patient-matched breast and brain metastasis cases) and (ii) unselected primary breast cancers (n = 336). NDRG1 was highly expressed in breast-to-brain metastases, as well as in high-grade primary breast cancers. High NDRG1 expression and also an absence of expression were associated with worse survival outcomes in both breast cancer and breast cancer brain metastasis patients. This establishes NDRG1 as a 'Goldilocks' protein, where too much or too little has a negative effect on survival. We pose that this accounts for its previous categorisation as both tumour suppressor and oncoprotein. Additionally, a shift in NDRG1 localisation with a gain of nuclear expression was seen at the brain metastasis stage. Significant survival benefit in cases expressing cytoplasmic NDRG1 was observed, whereas NDRG1 localisation in the nucleus showed a clear association with poorer survival. In vitro analyses revealed that hypoxic stress significantly elevated NDRG1 expression and resulted in its nuclear localisation. Our findings suggest NDRG1 expression and subcellular localisation are clinically relevant biomarkers for poor prognosis in breast cancer and breast cancer brain metastasis.
脑转移瘤是继发性脑肿瘤，具有侵袭性强和预后差的特点。乳腺癌是女性中最常见的扩散至脑部的原发性肿瘤之一。缺乏预测可能扩散至脑部的生物标志物以及治疗干预手段有限，是临床尚未满足的主要需求领域。我们研究了N - myc下调基因1（NDRG1）作为乳腺癌脑转移患者的临床相关生物标志物。使用免疫组织化学方法在两个临床队列的组织微阵列上研究NDRG1的表达：（i）脑转移性乳腺癌（n = 48）和脑转移瘤（n = 64；包括39例患者匹配的乳腺和脑转移病例的子集），以及（ii）未选择的原发性乳腺癌（n = 336）。NDRG1在乳腺至脑转移瘤以及高级别原发性乳腺癌中高表达。在乳腺癌和乳腺癌脑转移患者中，NDRG1高表达以及无表达均与较差的生存结果相关。这确立了NDRG1为一种“金发姑娘”蛋白，即过多或过少都会对生存产生负面影响。我们认为这解释了其先前被归类为肿瘤抑制因子和癌蛋白的原因。此外，在脑转移阶段观察到NDRG1定位发生改变，核表达增加。观察到表达细胞质NDRG1的病例有显著的生存获益，而NDRG1定位于细胞核则与较差的生存明显相关。体外分析显示，缺氧应激显著提高NDRG1表达并导致其核定位。我们的研究结果表明，NDRG1表达和亚细胞定位是乳腺癌和乳腺癌脑转移预后不良的临床相关生物标志物。
