Abstract 506: Targeting Y-box binding protein-1 (YB-1) overcomes drug resistance in triple-negative breast cancer.
Authors: Reipas Kristen , Stratford Anna , Astanehe Arezoo , Hu Kaiji , Dunn Sandra 
Published: August 2014

Abstract
Despite advances in treating breast cancer, disease recurrence rates remain high and secondary tumors are often resistant to chemotherapy and incurable. Currently, the treatment for triple-negative breast cancer (TNBC) relies upon conventional chemotherapeutics as there are no targeted therapies available. Although these tumors initially respond well, they paradoxically have the highest relapse rates.
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor abundantly expressed in TNBC (∼70% of patients). It is activated predominantly by phosphorylation via p90 ribosomal S6 kinase (RSK). Once activated it up-regulates the tumor-initiating-cell (TIC) marker CD44 and induces a TIC phenotype[1]. Due to their inherent drug-resistance, TICs survive chemotherapy and go on to drive relapse[2]. We recently identified RSK2 is critical to the survival of TNBC[3]. Inhibiting RSK2 blocks activation of YB-1 and induces apoptosis in TNBC, including CD44+/CD24- cells. Interestingly, inducing YB-1 is sufficient for transformation of human mammary epithelial cells into TNBC. Moreover, P-YB-1S102 is associated with poor overall survival (P&lt;0.001) and relapse (P&lt;0.001) in a cohort of 1057 patients with invasive breast cancer. Taken together, these data indicate YB-1 is important both in the genesis and maintenance of TNBC and implicate it as a key mediator of drug-resistance and relapse within this subtype.
Residual cells after paclitaxel or epirubicin have increased P-RSKS221/7, P-YB-1S102 and CD44 and retain mammosphere-forming capability. Cells expressing high P-YB-1S102 exclusively proliferate in the presence of these chemotherapies. Inhibiting YB-1 suppresses growth and induces apoptosis in residual cells and in CD44+/CD24–sorted cells. Pre-emptive knockdown of YB-1 prevents induction of CD44 and sensitizes cells to treatment with paclitaxel. Moreover, blocking RSK/YB-1 signaling suppresses growth and induces cell death in primary TNBC cells (x43) derived from a patient that eventually relapsed.
To investigate the role of RSK/YB-1 signaling in bona fide drug-resistant cells, we created paclitaxel-resistant SUM149 cells (SUM149-PTXR) which are cultured in 2 nM paclitaxel (PTX); a concentration that kills &gt;90% of paclitaxel-naive SUM149’s (SUM149-DMSO) by 72 hrs. These cells express increased P-RSKS221/7 and P-YB-1S102 without alterations in total protein levels. Despite their resistance to paclitaxel, these cells remain sensitive to RSK/YB-1 signaling inhibition. We are currently comparing the response of TNBC either with or without YB-1 to paclitaxel in an in vivo orthotopic xenograft model.
Collectively, these data indicate that inhibiting RSK/YB-1 signaling can overcome drug resistance and potentially reduce relapse in TNBC.
1.To K, Fotovati A et al. (2010) 2.Li X, Lewis MT et al. (2008) 3.Stratford A, Reipas K et al. (2012)
Citation Format: Kristen Reipas, Anna Stratford, Arezoo Astanehe, Kaiji Hu, Sandra Dunn. Targeting Y-box binding protein-1 (YB-1) overcomes drug resistance in triple-negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 506. doi:10.1158/1538-7445.AM2013-506