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YB-1 enhances ABCG2 expression in breast cancer to elicit chemoresistance that can be circumvented using RSK inhibitors

Davies, Alastair H. and Reipas, Kristen and Hu, Kaiji and Dunn, Sandra E. (2015) YB-1 enhances ABCG2 expression in breast cancer to elicit chemoresistance that can be circumvented using RSK inhibitors. Oncotarget, 6 (24). pp. 20570-20577. ISSN 1949-2553

Abstract

Despite advances in the treatment and management of breast cancer, recurrence remains a significant problem. Current dogma dictates that populations of drug resistant cells within a heterogeneous tumour are responsible for relapse. In this study, we demonstrate that the oncogenic transcription factor Y-box binding protein-1 (YB-1) regulates the expression of ABCG2, an ATP-binding transporter involved in multidrug resistance. Introducing YB-1 into human mammary epithelial cells (HMECs) was associated with increased ABCG2 promoter acetylation and gene expression. Accordingly, these cells acquired resistance to chemotherapeutic substrates of ABCG2, notably 5-fluoruracil, doxorubicin, and gefitinib. The acetylation-mediated relaxation of the ABCG2 promoter allowed for direct YB-1 binding and transcriptional regulation. As such, repressing YB-1 activation by RSK using the small molecule inhibitors BI-D1870 and luteolin led to a decrease in ABCG2 expression and resensitization of cells to chemotherapy. We found that treatment with luteolin or NVP-LJI308, a next-generation RSK inhibitor, was sufficient to induce apoptosis in triple-negative breast cancer cells. Moreover, RSK inhibition repressed soft agar colony growth and mammosphere formation. Relapse is believed to initiate from a drug resistant stem-like subpopulation within a heterogeneous tumour. Sorting for CD44+/CD49f+ cells revealed them to have an over 2-fold increase in ABCG2 expression relative to bulk tumour cells. As a result, they were refractory to traditional chemotherapy, but sensitive to the RSK inhibitors BI-D1870, NVP-LJI308, and luteolin. Therefore, targeting the RSK/YB-1 pathway inhibits ABCG2 and could represent a potential avenue to overcome multidrug resistance.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/22169

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