A novel EGR‐1 dependent mechanism for YB‐1 modulation of paclitaxel response in a triple negative breast cancer cell line
Open Access
- 12 April 2016
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 139 (5), 1157-1170
- https://doi.org/10.1002/ijc.30137
Abstract
Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required. One protein shown to be involved in drug resistance is Y-box binding protein 1 (YB-1). High levels of YB-1 have previously been associated with resistance to PTX in TNBCs. In this study, we aimed to determine mechanisms by which YB-1 confers PTX resistance. We generated isogenic TNBC cell lines that differed by YB-1 levels and treated these with PTX. Using microarray analysis, we identified EGR1 as a potential target of YB-1. We found that low EGR1 mRNA levels are associated with poor breast cancer patient prognosis, and that EGR1 and YBX1 mRNA expression was inversely correlated in a TNBC line and in a proportion of TNBC tumours. Reducing the levels of EGR1 caused TNBC cells to become more resistant to PTX. Given that PTX targets cycling cells, we propose a model whereby high YB-1 levels in some TNBC cells can lead to reduced levels of EGR1, which in turn promotes slow cell cycling and resistance to PTX. Therefore YB-1 and EGR1 levels are biologically linked and may provide a biomarker for TNBC response to PTX.Keywords
Funding Information
- Cancer Society of New Zealand (10/21, 10/03)
- Breast Cancer Cure
This publication has 46 references indexed in Scilit:
- Decline in the Use of Anthracyclines for Breast CancerJournal of Clinical Oncology, 2012
- Y-box-binding protein 1 (YB-1) and its functionsBiochemistry (Moscow), 2011
- Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in miceThe EMBO Journal, 2011
- Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapiesJCI Insight, 2011
- Identification of Y-Box Binding Protein 1 As a Core Regulator of MEK/ERK Pathway-Dependent Gene Signatures in Colorectal Cancer CellsPLoS Genetics, 2010
- Triple-negative breast cancerBreast Cancer Research, 2010
- Y-Box Binding Protein-1 Induces the Expression of CD44 and CD49f Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug ResistanceCancer Research, 2010
- A rapid and sensitive method to detect siRNA-mediated mRNA cleavage in vivo using 5′ RACE and a molecular beacon probeNucleic Acids Research, 2009
- Redefining prognostic factors for breast cancer: YB-1 is a stronger predictor of relapse and disease-specific survival than estrogen receptor or HER-2 across all tumor subtypesBreast Cancer Research, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001