Abstract
BackgroundDrug 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.MethodsWe 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.ResultsCharacterisation 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).ConclusionsThis 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 registrationClinicalTrials.gov identifier NCT00003012. Registered on 1 November 1999.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0676-6) contains supplementary material, which is available to authorized users.
Highlights
Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy
As the histone modification can be targeted with small-molecule inhibitors, it presents a possible means of reversing clinical anthracycline resistance
Generation and characterisation of epirubicin-resistant breast cancer cell lines Resistant cell lines generated from epirubicin-sensitive native cell lines MDA-MB-231, MCF7, SKBR3 and ZR75-1 exhibited 7- to 67-fold increased resistance to epirubicin (Fig. 1)
Summary
Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. A well-established in vitro mechanism of resistance involves activity of multidrug resistance genes 1 and 2/3 (MDR1 and MDR2/3, respectively), which bind nonspecifically to multiple drugs and actively export them across the cellular membrane [6, 7]. This results in decreased intra-cellular drug concentrations and cytotoxicity, the clinical relevance of MDR genes remains to be determined. Identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge
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