Y-box-binding protein 1 (YB1) in breast carcinomas: Relation to aggressive tumor phenotype and identification of patients at high risk for relapse E. Mylona a,d , S. Melissaris b,d , I. Giannopoulou b , I. Theohari b , C. Papadimitriou c , A. Keramopoulos c , L. Nakopoulou b, * a 5th Department of Internal Medicine, Evagelismos Hospital, Athens, Greece b 1st Department of Pathology, Medical School, University of Athens, 75 Mikras Asias Str., Goudi, GR-11527 Athens, Greece c Department of Clinical Therapeutics, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece Accepted 5 September 2013 Available online --- Abstract Aims: To investigate the expression pattern of Y-box-binding protein 1 (YB1) in breast carcinomas, its clinicopathological and prognostic value, and its association with the breast cancer stem cell phenotype [CD44 þ /CD24 /low ]. Methods and results: Immunohistochemistry was performed on 225 paraffin embedded specimens of invasive breast carcinomas to detect the expression of the proteins YB1, ER, PR, HER2, p53, Ki67, bcl-2, CD44 and CD24. YB1 protein was detected in the nuclei, the cyto- plasm and the stroma of the tumor cells. Cytoplasmic YB1 was detected more often in carcinomas of ductal type ( p ¼ 0.002), of higher nuclear grade ( p < 0.001), with lack of ER expression ( p ¼ 0.002), positive expression of p53 and Ki67 ( p ¼ 0.002 and p ¼ 022, respec- tively), and with present CD44 þ /CD24 /low breast cancer stem cells ( p ¼ 0.001), while its association with bcl-2 was found to be inverse ( p ¼ 0.042). Nuclear YB1 was found to exert unfavorable impact on the disease-free survival of the unselected patients ( p ¼ 0.05) and the patients having been subjected to adjuvant chemotherapy and radiotherapy ( p ¼ 0.036 and p ¼ 0.05, respectively). Conclusions: Cytoplasmic YB1 is associated with an aggressive and “stem cell-like” tumor phenotype, while nuclear localization discrim- inates patients at high risk for recurrence, especially those who are subjected to chemo- and radiotherapy. Ó 2013 Published by Elsevier Ltd. Keywords: Y-box-binding protein; Breast cancer; Immunohistochemistry; Recurrence-free survival; Chemotherapy; Radiotherapy Introduction Y-box-binding protein YB1 belongs to the Y-box tran- scription factors which were first identified by their ability to bind the Y-box promoter element, regulating expression of various genes. 1 Despite its proven nuclear function in transcriptional control, the majority of YB1 is found in the cytoplasm, in complexes with mRNA. 1,2 Thus, by bind- ing to DNA and RNA, YB1 is involved in almost all DNA- and mRNA-dependent processes such as DNA replication, repair and transcription as well as mRNA splicing and translation. 1,2 YB1 is considered to be a marker of tumorigenesis. Bergmann et al., demonstrated that elevated YB1 expression in mammary glands induces invasive breast car- cinomas in lactating transgenic mice. 3 In human cancer tis- sues, YB1 overexpression has been associated with an aggressive tumor phenotype 4 as well as with worse prognosis. 4e6 Increased YB1 levels in human breast carcinomas have been associated with the intrinsic multidrug resistance gene 1 (MDR1) expression, suggesting its implication in the acquisition of drug resistance. 7 However, it remains un- clear whether the association of YB1 with poor prognosis is due to this effect, or due to other factors affecting tumor growth, invasion and metastasis. For example, YB1 overex- pression has been reported to stimulate the proliferation of MCF-7 breast carcinoma cells, suggesting that YB1 plays a key role in cell growth. 8 In addition, recent studies have provided evidence that enforced expression of YB1 in non invasive breast epithelial cells induced an epithe- lialemesenchymal transition (EMT), 9 a key developmental * Corresponding author. Tel.: þ30 2107462116; fax: þ30 2107462157. E-mail address: lnako@med.uoa.gr (L. Nakopoulou). d Both authors have equally contributed to this work. 0748-7983/$ - see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.ejso.2013.09.008 Available online at www.sciencedirect.com ScienceDirect EJSO xx (2013) 1e8 www.ejso.com Please cite this article in press as: Mylona E, et al., Y-box-binding protein 1 (YB1) in breast carcinomas: Relation to aggressive tumor phenotype and identification of patients at high risk for relapse, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.09.008