Discovery of Proteins Responsible for Resistance to Three Chemotherapy Drugs in Breast Cancer Cells Using Proteomics and Bioinformatics Analysis

Hyo Kyeong Cha,Hyeyoon Kim,Kyung-Min Lee,Seongmin Cheon,Dohyun Han,Han Suk Ryu

doi:10.3390/molecules27061762

Hyo Kyeong Cha, Hyeyoon Kim + Show 4 more

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https://doi.org/10.3390/molecules27061762

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Abstract

Chemoresistance is a daunting obstacle to the effective treatment of breast cancer patients receiving chemotherapy. Although the mechanism of chemotherapy drug resistance has been explored broadly, the precise mechanism at the proteome level remains unclear. Especially, comparative studies between widely used anticancer drugs in breast cancer are very limited. In this study, we employed proteomics and bioinformatics approaches on chemoresistant breast cancer cell lines to understand the underlying resistance mechanisms that resulted from doxorubicin (DR), paclitaxel (PR), and tamoxifen (TAR). In total, 10,385 proteins were identified and quantified from three TMT 6-plex and one TMT 10-plex experiments. Bioinformatics analysis showed that Notch signaling, immune response, and protein re-localization processes were uniquely associated with DR, PR, and TAR resistance, respectively. In addition, proteomic signatures related to drug resistance were identified as potential targets of many FDA-approved drugs. Furthermore, we identified potential prognostic proteins with significant effects on overall survival. Representatively, PLXNB2 expression was associated with a highly significant increase in risk, and downregulation of ACOX3 was correlated with a worse overall survival rate. Consequently, our study provides new insights into the proteomic aspects of the distinct mechanisms underlying chemoresistance in breast cancer.

Highlights

Breast cancer accounts for roughly 30% of all cancers in women worldwide and has a15% death rate; further, incidence rates are increasing at a rate of about 0.5% per year [1]
tandem mass tag (TMT) 6-plex3 wof a20s used to compare parental MCF-7 and resistant MCF-7 of each of the three anticancer drugs, and TMT 10-plex was used for direct comparisons between three drug-resistant aMnCdFT-7McTel1ls0.-Tphleexewxpaesruimseedntfaolrpdroirceecdtucroems pfoarripsroontseobmetiwc aenenalythsriseearderiullgu-srtersaitsetdanitnMFiCguFr-7e c1eal.ls
In subgroups of patients treated with chemotherapy (332 patients in Metabric), we found that high plexin-B2 (PLXNB2) expression was associated with shorter overall survival (OS), whereas downregulation of acyl-coenzyme A oxidase 3 (ACOX3) predicted shorter OS in patients treated with chemotherapy (Figure 6c,d)

Summary

Introduction

Breast cancer accounts for roughly 30% of all cancers in women worldwide and has a15% death rate; further, incidence rates are increasing at a rate of about 0.5% per year [1]. Breast cancer comprises a heterogeneous group of tumor subtypes, whether defined by the histopathology of the primary tumor, the expression pattern of hormone receptors (estrogen and/or progesterone receptors; ER/PR) and epidermal growth factor receptor 2 (HER2), genetic alterations of transcriptomic traits These patient-to-patient differences, known as ‘intertumoral heterogeneity’, largely affect patient prognosis and treatment options [2–4]. Many studies reported that breast cancers are heterogeneous, with a patient’s primary tumor and individual metastases consisting of many different cells or subclones with different gene expression profiles [2–4] These differences within the tumor are referred to as intratumor heterogeneity, which is caused by a combination of extrinsic factors from the tumor microenvironment and intrinsic parameters including genetic, epigenetic, and transcriptomic traits, the ability of proliferation, migration, and invasion, cell plasticity, and the extent of stemness [2–4]. These heterogeneities endow tumors with multiple capabilities and biological characteristics, making them more prone to metastasis, recurrence, and drug resistance [5]

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