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The Y-box binding protein 1 (YB-1) is a multifunctional protein that affects transcription, splicing, and translation. Overexpression of YB-1 in breast cancers causes cisplatin resistance. The exact mechanism by which YB-1 confers cisplatin resistance is unknown. The aim of the present study was to identify, using mass spectrometry, proteins that interact with YB-1 that are important for cisplatin resistance in two breast cancer cell lines, namely MCF7 and MDA-MB-231. A tagged YB-1 construct was used to identify proteins interacting directly with YB-1 in breast cancer cells. We then focused on proteins that are potentially involved in breast cancer progression based on the ONCOMINE public microarray database. Genes encoding for these YB-1-interacting proteins were examined in the public NCBI comparative genomic hybridization database to determine whether they are localized to regions of chromosomes that are rearranged in breast cancer tissues. From these analyses, we generated a list of proteins potentially involved in cisplatin resistance. Cisplatin dose–response curves were constructed in MCF7 and MDA-MB-231 transfected with four siRNA corresponding to each of these YB-1 interactors to identify proteins significantly affecting cisplatin sensitivity upon gene silencing. Depletion of only the X-linked ribosomal protein S4 (RPS4X) resulted in consistent resistance to cisplatin in both cell lines with at least three different siRNA sequences against RPS4X. Further analyses indicated that the knock down of RPS4X decreased DNA synthesis, induced cisplatin resistance, and is equivalent to the overexpression of YB-1 in both MCF7 and MDA-MB-231 cells. These results suggest that the RPS4X/YB-1 complex is a significant potential target to counteract cisplatin resistance in breast cancer. (Cancer Sci 2011; 102: 1410–1417)