Differential Expression and Pathway Analysis in Drug-Resistant Triple-Negative Breast Cancer Cell Lines Using RNASeq Analysis.

Safa Shaheen,Shaheen Shah,Febin Fawaz,Dietrich Büsselberg

doi:10.3390/ijms19061810

Abstract

Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as high amount of molecular variability. Drug resistance also contributes to treatment unresponsiveness. We studied differentially expressed genes, their biological roles, as well as pathways from RNA-Seq datasets of two different TNBC drug-resistant cell lines of Basal B subtype SUM159 and MDA-MB-231 treated with drugs JQ1 and Dexamethasone, respectively, to elucidate the mechanism of drug resistance. RNA sequencing(RNA-Seq) data analysis was done using edgeR which is an efficient program for determining the most significant Differentially Expressed Genes (DEGs), Gene Ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. iPathway analysis was further used to obtain validated results using analysis that takes into consideration type, function, and interactions of genes in the pathway. The significant similarities and differences throw light into the molecular heterogeneity of TNBC, giving clues into the aspects that can be focused to overcome drug resistance. From this study, cytokine-cytokine receptor interaction pathway appeared to be a key factor in TNBC drug resistance.

Highlights

Breast cancer represents one of the most common cancers in women and is a major life-threatening disease
Drugs normally targeted to the receptors do not apply to Triple-Negative Breast Cancer (TNBC) as they lack the three receptors, namely the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [2]
Targeted therapy by developing targeted agents like poly(ADP-ribose) polymerase-1 (PARP-1), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 2 (FGFR2), vascular endothelial growth factor (VEGF), and the mammalian target of rapamycin in combination with chemotherapy seems promising in treatment of TNBC [3]

Summary

Introduction

Breast cancer represents one of the most common cancers in women and is a major life-threatening disease. Targeted therapy by developing targeted agents like poly(ADP-ribose) polymerase-1 (PARP-1), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 2 (FGFR2), vascular endothelial growth factor (VEGF), and the mammalian target of rapamycin (mTOR) in combination with chemotherapy seems promising in treatment of TNBC [3]. Pathways such as NOTCH signaling pathway and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling pathway are being targeted for overcoming drug resistance in cancer therapy [6,7]. Drugs targeting pathways are being developed such as those targeting the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway for the treatment of TNBC and shows promise as stated by Gradishar W.J. et al [8]

Objectives

Methods

Results