A novel EGR‐1 dependent mechanism for YB‐1 modulation of paclitaxel response in a triple negative breast cancer cell line

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.

Comprehensive tissue-specific gene set enrichment analysis and transcription factor analysis of breast cancer by integrating 14 gene expression datasets

“…The following are the four members of this family: EGR1, EGR2, EGR3 and EGR4. All of these TFs have been proven to correlate with breast cancer pathogenesis and prognosis [25–28]. In addition, this study found the following tissue specific TFs that were not reported in breast cancer: ATOH8, DMRT2, TBX15 and ZNF367.…”

miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4

“…Herein, our data show that restoring miR-137 expression in BC cells led to the suppression of DUSP4 expression. DUSP4 upregulation has been reported in relation to drug resistance and patient outcome in BC [42][43][44] . Silencing DUSP4 significantly sensitized BC cells to trastuzumab 45 .…”

Oncogenic Y‐box binding protein‐1 as an effective therapeutic target in drug‐resistant cancer

“…Among the numerous human tumor types, the clinical significance of YBX1 has been most extensively studied in breast cancer (Table , Doc ). Enhanced expression of YBX1 is predictive of poor outcomes in patients with breast cancer . Adjuvant endocrine therapy and chemotherapy treatments have been used extensively in the treatment of breast cancer .…”

“…Enhanced expression of YBX1 is predictive of poor outcomes in patients with breast cancer. [36][37][38][39][40][41] Adjuvant endocrine therapy and chemotherapy treatments have been used extensively in the treatment of breast cancer. 42,43 However, the emergence of refractory tumors is a major complication for breast cancer patients treated with adjuvant endocrine therapy.…”