Davies, Alastair H., Reipas, Kristen, 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