Trial reportBreast cancer research : BCR2016
Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer.
Trial report in Breast cancer research : BCR, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00003012 (A Prospective Randomized Comparison of CMF Versus Sequential Epirubicin Followed by SMF as Adjuvant Chemotherapy for Women With Early Breast Cancer), which is not on this map. Cited by 15 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Prospective Randomized Comparison of CMF Versus Sequential Epirubicin Followed by SMF as Adjuvant Chemotherapy for Women With Early Breast Cancer
Who cites it
15 citing papers in PubMed, 34 citations in OpenAlex.
- Evaluating the prognostic significance of HIST1H4C in breast cancer: implications for neoadjuvant therapy.Scientific reports · 2026Article
- Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.Cancer drug resistance (Alhambra, Calif.) · 2026Article
- Race-related host and microbe transcriptomic signatures in triple-negative breast cancer.NPJ breast cancer · 2025Article
- A comprehensive landscape analysis of autophagy in cancer development and drug resistance.Frontiers in immunology · 2024Article
- DoxoDB: A Database for the Expression Analysis of Doxorubicin-Induced lncRNA Genes.Non-coding RNA · 2023Article
- Chemotherapy induces ACE2 expression in breast cancer via the ROS-AKT-HIF-1α signaling pathway: a potential prognostic marker for breast cancer patients receiving chemotherapy.Journal of translational medicine · 2022Article
- Canady Helios Cold Plasma Induces Breast Cancer Cell Death by Oxidation of Histone mRNA.International journal of molecular sciences · 2021Article
- Proteomic Analysis on Anti-Proliferative and Apoptosis Effects of Curcumin Analog, 1,5-bis(4-Hydroxy-3-Methyoxyphenyl)-1,4-Pentadiene-3-One-Treated Human Glioblastoma and Neuroblastoma Cells.Frontiers in molecular biosciences · 2021Article
- H2AX Promoter Demethylation at Specific Sites Plays a Role in STAT5-Induced Tumorigenesis.Journal of mammary gland biology and neoplasia · 2020Article
- Doxorubicin induces large-scale and differential H2A and H2B redistribution in live cells.PloS one · 2020Article
- PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.Therapeutic advances in medical oncology · 2020Article
- Expression and potential prognostic value of histone family gene signature in breast cancer.Experimental and therapeutic medicine · 2019Article
- Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours.Breast cancer research : BCR · 2019Article
- HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells.Oncotarget · 2017Article
- Luminal STAT5 mediates H2AX promoter activity in distinct population of basal mammary epithelial cells.Oncotarget · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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