title: The prognostic effect of DDX3 upregulation in distant breast cancer metastases.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marise R
authors.initials: MR
authors.lastname: Heerma van Voss
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Willemijne A M E
authors.initials: WA
authors.lastname: Schrijver
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Ter Hoeve
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Laurien D
authors.initials: LD
authors.lastname: Hoefnagel
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Quirine F
authors.initials: QF
authors.lastname: Manson
authors.affiliation: Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.affiliation: 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.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. P.J.vanDiest@umcutrecht.nl.|Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. P.J.vanDiest@umcutrecht.nl.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
keywords: Brain metastasis; Breast cancer; DDX3; DDX3X; DEAD box RNA helicases; Metastasis