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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Marsela Braunstein, Linda Liao, Nicola Lyttle, Nazleen Lobo, Karen J. Taylor, Paul M. Krzyzanowski, Irina Kalatskaya, Cindy Q. Yao, Lincoln D. Stein, Paul C. Boutros, Christopher J. Twelves, Richard Marcellus, John M. S. Bartlett, Melanie Spears

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Trial registration

ClinicalTrials.gov identifier NCT00003012. Registered on 1 November 1999.
Appendix
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Metadata
Title
Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer
Authors
Marsela Braunstein
Linda Liao
Nicola Lyttle
Nazleen Lobo
Karen J. Taylor
Paul M. Krzyzanowski
Irina Kalatskaya
Cindy Q. Yao
Lincoln D. Stein
Paul C. Boutros
Christopher J. Twelves
Richard Marcellus
John M. S. Bartlett
Melanie Spears
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0676-6

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