Heerma van Voss Marise R, Schrijver Willemijne A M E, Ter Hoeve Natalie D, Hoefnagel Laurien D, Manson Quirine F, van der Wall Elsken, Raman Venu, van Diest Paul J
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Radiology and Radiological Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Clin Exp Metastasis. 2017 Jan;34(1):85-92. doi: 10.1007/s10585-016-9832-8. Epub 2016 Dec 20.
Metastatic breast cancer remains one of the leading causes of death in women and identification of novel treatment targets is therefore warranted. Functional studies showed that the RNA helicase DDX3 promotes metastasis, but DDX3 expression was never studied in patient samples of metastatic cancer. In order to validate previous functional studies and to evaluate DDX3 as a potential therapeutic target, we investigated DDX3 expression in paired samples of primary and metastatic breast cancer. Samples from 79 breast cancer patients with distant metastases at various anatomical sites were immunohistochemically stained for DDX3. Both cytoplasmic and nuclear DDX3 expression were compared between primary and metastatic tumors. In addition, the correlation between DDX3 expression and overall survival was assessed. Upregulation of cytoplasmic (28%; OR 3.7; p = 0.002) was common in breast cancer metastases, especially in triple negative (TN) and high grade cases. High cytoplasmic DDX3 levels were most frequent in brain lesions (65%) and significantly correlated with high mitotic activity and triple negative subtype. In addition, worse overall survival was observed for patients with high DDX3 expression in the metastasis (HR 1.79, p = 0.039). Overall, we conclude that DDX3 expression is upregulated in distant breast cancer metastases, especially in the brain and in TN cases. In addition, high metastatic DDX3 expression correlates with worse survival, implying that DDX3 is a potential therapeutic target in metastatic breast cancer, in particular in the clinically important group of TN patients.
转移性乳腺癌仍然是女性死亡的主要原因之一，因此有必要确定新的治疗靶点。功能研究表明，RNA解旋酶DDX3促进转移，但从未在转移性癌症患者样本中研究过DDX3的表达。为了验证先前的功能研究并评估DDX3作为潜在治疗靶点的可能性，我们研究了原发性和转移性乳腺癌配对样本中DDX3的表达。对79例在不同解剖部位有远处转移的乳腺癌患者的样本进行了DDX3免疫组织化学染色。比较了原发性肿瘤和转移性肿瘤中细胞质和细胞核DDX3的表达。此外，还评估了DDX3表达与总生存期之间的相关性。细胞质上调（28%；OR 3.7；p = 0.002）在乳腺癌转移中很常见，尤其是在三阴性（TN）和高级别病例中。高细胞质DDX3水平在脑转移灶中最为常见（65%），并与高有丝分裂活性和三阴性亚型显著相关。此外，转移灶中DDX3表达高的患者总生存期较差（HR 1.79，p = 0.039）。总体而言，我们得出结论，DDX3表达在远处乳腺癌转移中上调，尤其是在脑转移和TN病例中。此外，高转移性DDX3表达与较差的生存率相关，这意味着DDX3是转移性乳腺癌的潜在治疗靶点，特别是在临床上重要的TN患者群体中。
