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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer
Marsela Braunstein1,2, Linda Liao3, Nicola Lyttle4
1Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Toronto, ON, M5G 0A3, Canada. marsela.braunstein@oicr.on.ca.
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.
Insights
Targeting histone pathways with small-molecule inhibitors can reverse anthracycline resistance in breast cancer. This study identified histone H2A and H2B gene deregulation as a key mechanism contributing to drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance in breast cancer is a major obstacle to chemotherapy.
- Upregulation of multidrug resistance genes is implicated, but clinical relevance is unclear.
- Identifying targets to overcome anthracycline resistance is a critical challenge.
Purpose of the Study:
- To identify pathways contributing to anthracycline resistance in breast cancer.
- To investigate the potential of targeting these pathways to reverse drug resistance.
- To assess the clinical relevance of identified pathways in patient outcomes.
Main Methods:
- Generated epirubicin-resistant breast cancer cell lines (MDA-MB-231, MCF7, SKBR3, ZR-75-1).
- Utilized gene expression analysis to identify molecular pathways involved in resistance.
- Employed small-molecule inhibitors to test resistance reversal and assessed clinical relevance in the BR9601 trial.
Main Results:
- Epirubicin-resistant cells exhibited cross-resistance to doxorubicin and SN-38, with altered apoptosis and cell-cycle profiles.
- Gene expression analysis revealed deregulation of histone H2A and H2B genes in resistant cell lines.
- Histone deacetylase inhibitors reversed resistance and were cytotoxic; low expression of an 18-gene histone module correlated with better anthracycline treatment benefit in patients.
Conclusions:
- Histone modification pathways are key contributors to anthracycline resistance in breast cancer.
- Targeting histone modifications with small-molecule inhibitors offers a potential strategy to reverse clinical drug resistance.
- Established model systems facilitate further investigation into breast cancer drug resistance mechanisms.
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