Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer

Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that...

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Bibliographic Details
Published in:Breast cancer research : BCR 2016-02, Vol.18 (1), p.16, Article 16
Main Authors: Braunstein, Marsela, Liao, Linda, Lyttle, Nicola, Lobo, Nazleen, Taylor, Karen J, Krzyzanowski, Paul M, Kalatskaya, Irina, Yao, Cindy Q, Stein, Lincoln D, Boutros, Paul C, Twelves, Christopher J, Marcellus, Richard, Bartlett, John M S, Spears, Melanie
Format: Article
Language:English
Subjects:
Adult
Analysis
Anthracyclines - administration & dosage
Apoptosis - drug effects
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Cancer
Care and treatment
Chemotherapy
Complications and side effects
Doxorubicin - administration & dosage
Drug resistance
Drug Resistance, Neoplasm - genetics
Epirubicin - administration & dosage
Female
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Genetic aspects
Health aspects
Histone Deacetylase Inhibitors - administration & dosage
Histones - biosynthesis
Histones - genetics
Humans
Irinotecan
MCF-7 Cells
Middle Aged
Signal Transduction - drug effects
Young Adult
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Summary:Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13-0.96, p = 0.042). This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999.
ISSN:1465-542X
1465-5411
1465-542X
DOI:10.1186/s13058-016-0676-6