Distinct Genes Related to Drug Response Identified in ER Positive and ER Negative Breast Cancer Cell Lines

Kui Shen,Zhenyu Ding,Paul R Ervin,Nan Song,Chunqiao Tian,Stacey L Brower,Shara D Rice,David A Gingrich,Michael J Gabrin,Dakun Wang,George Tseng,Zhibao Mi

doi:10.1371/journal.pone.0040900

Kui Shen, Zhenyu Ding + Show 10 more

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https://doi.org/10.1371/journal.pone.0040900

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Abstract

Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER) positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel). We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK) were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in multidrug response in ER positive and ER negative breast cells.

Highlights

A multitude of chemotherapeutic drugs have been widely used in various combinations to treat breast cancer patients, the response to chemotherapy treatment varies considerably among patients; even among patients who have identical histological type
Since estrogen receptor (ER) negative cells generally are more responsive than ER positive cells and ER status is a strong factor associated with drug response, genes identified from mixed breast tumors tend to be related to ER status, and may be less informative after stratifying by ER subtype
Consistent with other studies [19], our analysis showed that ER negative cell lines tended to be more responsive to chemotherapy drugs

Summary

Introduction

A multitude of chemotherapeutic drugs have been widely used in various combinations to treat breast cancer patients, the response to chemotherapy treatment varies considerably among patients; even among patients who have identical histological type. Genomic research suggests that response to treatment is significantly related to intrinsic molecular characteristics of the tumor. Studying these genes has important biological significance and potential clinical utility. During the past several years, various microarray expression studies have identified genes whose expression is related to response to chemotherapeutic agents [1,2,3,4,5]. Most of these studies did not take into account the heterogeneity of breast cancer. A comprehensive analysis of identifying genes related to drug response in ER positive and ER negative has yet to be performed

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