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Here, we aim to take a system\u2010level approach to explore a mechanism by which stromal cells induce chemoresistance in cancer cells and subsequently identify a drug that can inhibit such interaction. Using a proteomic dataset containing quantitative data on secretome of stromal cells, we performed multivariate analyses and found that bone\u2010marrow mesenchymal stem cells (BM\u2010MSCs) play the most protective role against chemotherapeutics. Pathway enrichment tests showed that secreted cytokines from BM\u2010MSCs activated 4 signaling pathways including Janus kinase\u2010signal transducer and activator of transcription, phosphatidylinositol 3\u2010kinase\u2010protein kinase B, and mitogen\u2010activated protein kinase, transforming growth factor\u2010\u03b2 in cancer cells collectively leading to nuclear factor\u00a0kappa\u2010light\u2010chain\u2010enhancer of activated B cells (NF\u2010kB) transcription factor activation. Based\u00a0on the data from integrated Library of Integrated Network\u2010Based Cellular Signatures (iLINCs) program, we found that among different drugs, valproic acid (VA) affected the expression of 34 genes within the identified pathways that are activated by stromal cells. Our in vitro experiments confirmed that VA inhibits NF\u2010kB activation in cancer cells. In addition, analyzing gene expression data in patients taking oral VA showed that this drug decreased expression of antioxidant enzymes culminating in increased oxidative stress in tumor cells. These results suggest that VA confines the protective role of stromal cells by inhibiting the adaptation mechanisms toward oxidative stress which is potentiated by stromal cells. Since VA is an already prescribed drug manifesting anticancer effects, this study provides a mechanistic insight for combination of VA with chemotherapy in the clinical setting.<\/jats:p>","DOI":"10.1002\/jcb.27196","type":"journal-article","created":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T20:14:43Z","timestamp":1530216883000},"page":"9270-9283","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Valproic acid inhibits the protective effects of stromal cells against chemotherapy in breast cancer: Insights from proteomics and systems biology"],"prefix":"10.1002","volume":"119","author":[{"given":"Farnaz","family":"Barneh","sequence":"first","affiliation":[{"name":"Department of Basic Sciences Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences Tehran Iran"},{"name":"Physiology and Pharmacology Department Pasteur Institute of Iran Tehran Iran"},{"name":"Drug Design and\u00a0Bioinformatics Unit, Medical Biotechnology Department Biotechnology Research Center, Pasteur Institute of Iran Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-7009","authenticated-orcid":false,"given":"Mona","family":"Salimi","sequence":"additional","affiliation":[{"name":"Physiology and Pharmacology Department Pasteur Institute of Iran Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Goshadrou","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoo","family":"Ashtiani","sequence":"additional","affiliation":[{"name":"Drug Design and\u00a0Bioinformatics Unit, Medical Biotechnology Department Biotechnology Research Center, Pasteur Institute of Iran Tehran Iran"},{"name":"Department of Computer Science and Statistics Faculty of Mathematics, K. 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