PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer

Joint Research Laboratory of the Hungarian Academy of Sciences and the Semmelweis University, Semmelweis University 1st Department of Pediatrics, Budapest, Hungary.
British Journal of Cancer (Impact Factor: 4.84). 12/2009; 102(2):361-8. DOI: 10.1038/sj.bjc.6605478
Source: PubMed


To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation.
We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples.
After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001).
Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.

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Available from: Balázs Györffy, Mar 31, 2015
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    • "DNA-bound anthracycline binds DNA topoisomerase II, inducing DNA cleavage in an ATP-dependent manner [2]. Anthracycline resistance might be mediated through overexpression of P-glycoprotein [3], [4], [5], lung resistance protein [6] and multidrug-resistance proteins [7], [8], proteasome subunits [9], increases in antioxidant defenses [10], alterations in apoptotic signaling and TOP2 activity [5], [11], [12]. Most recently, over-expression of genes in the chromosomal region 8q22 have been shown to be associated with anthracycline resistance. "
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    ABSTRACT: Developing chemotherapy resistant cell lines can help to identify markers of resistance. Instead of using a panel of highly heterogeneous cell lines, we assumed that truly robust and convergent pattern of resistance can be identified in multiple parallel engineered derivatives of only a few parental cell lines. Parallel cell populations were initiated for two breast cancer cell lines (MDA-MB-231 and MCF-7) and these were treated independently for 18 months with doxorubicin or paclitaxel. IC50 values against 4 chemotherapy agents were determined to measure cross-resistance. Chromosomal instability and karyotypic changes were determined by cytogenetics. TaqMan RT-PCR measurements were performed for resistance-candidate genes. Pgp activity was measured by FACS. All together 16 doxorubicin- and 13 paclitaxel-treated cell lines were developed showing 2-46 fold and 3-28 fold increase in resistance, respectively. The RT-PCR and FACS analyses confirmed changes in tubulin isofom composition, TOP2A and MVP expression and activity of transport pumps (ABCB1, ABCG2). Cytogenetics showed less chromosomes but more structural aberrations in the resistant cells. We surpassed previous studies by parallel developing a massive number of cell lines to investigate chemoresistance. While the heterogeneity caused evolution of multiple resistant clones with different resistance characteristics, the activation of only a few mechanisms were sufficient in one cell line to achieve resistance.
    Full-text · Article · Feb 2012 · PLoS ONE
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    • "The next generation of signatures ought to focus on specific drugs within a given subtype of breast cancer, as the predictors of response to chemotherapy in ER-positive and ER-negative breast cancers appear to be fundamentally different [19]. Furthermore, potential mechanisms of resistance to chemotherapy identified by orthogonal methods (for example, RNA interference screens [105], microarray-based comparative genomic hybridization [106,107], proteomic analyses [108], and hypothesis-driven studies [109]) may be used as the basis for the development of multigene predictive signatures. With the availability of multiple microarray datasets from retrospective cohorts and clinical trials in the public domain, novel signatures derived from analyses using orthogonal methods can be tested in a timely fashion. "
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    ABSTRACT: Breast cancer comprises a collection of diseases with distinctive clinical, histopathological, and molecular features. Importantly, tumors with similar histological features may display disparate clinical behaviors. Gene expression profiling using microarray technologies has improved our understanding of breast cancer biology and has led to the development of a breast cancer molecular taxonomy and of multigene 'signatures' to predict outcome and response to systemic therapies. The use of these prognostic and predictive signatures in routine clinical decision-making remains controversial. Here, we review the clinical relevance of microarray-based profiling of breast cancer and discuss its impact on patient management.
    Preview · Article · Jun 2011 · Breast cancer research: BCR
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    • "Altered expression of the PSMB4 gene was recently observed in association with various tumor types (glioblastoma, ovarian carcinoma, hepatocarcinoma, prostate carcinoma) through different approaches [36-39]. Interestingly, another human gene coding for the 20S proteasome unit β-type 7 (PSMB7), is associated with anthracycline resistance and is a prognostic biomarker in breast cancer [40]. "
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    ABSTRACT: The ubiquitin(Ub)-proteasome pathway is implicated in the regulation of a variety of cellular functions and plays a major role in stress response in eukaryotic cells, by targeting misfolded and damaged proteins for degradation. In addition, in the presence of DNA damage, the Ub-proteasome system regulates proteins involved in sensing, repairing, and/or tolerating the damage. Antitumor agents such as cisplatin can activate the pathway, but the role of specific pathway components in cell sensitivity/response to the drug is not known. Since platinum compounds represent clinically relevant antitumor agents and a major limitation to their use is the development of drug resistance, there is an urgent need for identifying targets for improving their efficacy. In the present study, we performed a genome-wide screening for sensitivity to cisplatin using non-essential haploid deletion mutants of the fission yeast Schizosaccharomyces pombe, belonging to a collection of haploid strains constructed through homologous recombination. Using this approach, we identified three Ub-proteasome mutants exhibiting hypersensitivity to cisplatin (ubp16, ubc13 and pmt3) and ten mutants (including ufd2, beta7 20S, rpt6/let1) resistant to the drug. In addition, the importance of lub1 gene emerged from the comparison between the present screening and gene expression profile data previously obtained in fission yeast. The factors identified in the present study allowed us to highlight most finely the close relationship between the Ub-proteasome system and DNA damage response mechanisms, thus establishing a comprehensive framework of regulators likely relevant also in higher eukaryotes. Our results provide the proof of principle of the involvement of specific genes modulated by cisplatin treatment in cell response to the drug, suggesting their potential role as targets for modulating cisplatin sensitivity. In this regard, the prospective identification of novel targets for modulation of cisplatin sensitivity in an eukaryotic model organism appears particularly intriguing towards the discovery of strategies to overcome cisplatin resistance in human tumors.
    Full-text · Article · Jan 2011 · BMC Genomics
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